The Protective Effects of Melatonin against Brain Disorders Induced by the Western Diet in Male Rats Текст научной статьи по специальности «Фундаментальная медицина»

2023, Scienceline Publication

Worlds Veterinary Journal

World Vet J, 13(2): 264-284, June 25, 2023

DOI: https://dx.doi.org/10.54203/scil.2023.wvj29

The Protective Effects of Melatonin against Brain Disorders Induced by the Western Diet in Male Rats

Ahmed Raheem Rayshan © , Ammar A. Abdulwahid * © , and Alyaa Abdulhussein Alsaedi3 ©

'Scientific affairs department, University of Al-Qadisiyah, Al-Diwaniyah, Al-Qadisiyyah, Iraq

2Lecturer, Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq 3Lecturer, Department of Microbiology, College of Veterinary Medicine, University of Al-Qadisiyah, Iraq

*Corresponding author's Email: [email protected] ABSTRACT

Globally, the effects of consuming a diet rich in fat have gained great concerted attention. The current study was conducted to evaluate the protective effects of melatonin on neurological disorders induced by the western diet in rats. A total of 30 adult male white local Iraqi rats were randomly assigned to three equal groups, including control (CC), high-fat diet (HFD), and melatonin group (HFD+M, a high-fat diet along with intraperitoneal injections of 10 mg/kg body weight melatonin) for 8 weeks. The rats were analyzed in terms of brain tissue concentration of dopamine, tumor necrosis factor (TNF), and nervous system impairment using Barns maze task and elevated plus maze. The findings revealed a significant decline in the dopamine concentration of the HFD group after 8 weeks of treatment, compared to CC and HFD+M groups. Moreover, there was a significant increase in brain TNF-a concentration in the group fed HFD, compared with CC and HFD+M. Finally, the melatonin treatment significantly reduced spatial memory impairments and anxiety induced by HFD in rats. After 8 weeks, the histological examination revealed that brain section rats on an HFD indicated significant congestion in the blood vessels with marked cerebral edema, where there was a dilation of Virchow-Robin space, severe congestion, and infiltration of inflammatory cells in the meninges. The HFD+M groups showed normal meninges without any inflammatory exudate except for a few congestions in the blood vessels and no or mild vacuolations in the cerebral tissue, gliosis, and astrocytosis. In contrast, male rats fed an HFD showed vacuolation and aerophagia in brain tissue and a marked aggregation of the proliferation of astrocytes and a proliferation of microglial cells in the cerebral. In conclusion, HFD impairs brain neurotransmitters, induces pro-inflammatory changes, and affects learning ability and memory by changing the structure of neural tissue. Melatonin can ameliorate HFD-caused effects.

Keywords: Brain, High-fat diet, Inflammatory cells, Learning ability, Melatonin, Nervous system INTRODUCTION

The earliest definition of a high-fat diet (HFD) as a nutritional strategy to enhance obesity was published in 1959 (Masek and Fabry, 1959). The HFD can be well observed in the Western, high-energy, high-fat, cafeteria, and high-fat sugar diets. The precise nutrition structure of the control and fat diets, including the quantity and types of carbohydrates of fats, may vary and is not extensively detailed (Mozaffarian et al., 2011; Mota et al., 2023). It is unknown whether strains, ages, and species of animals may affect the outcomes of consuming HFD experiments or whether adjusting critical parameters, such as weight, behaviors, and memory, may be affected by the type and duration of diet exposure (Abbott et al., 2019). Obesogenic feed often contains 60% of total calories as fat, compared to 30-40% fat in a typical Western diet (Lai et al., 2014).

During lipopolysaccharide-induced end toxemia, the spleen releases newly-produced tumor necrosis factor-alpha (TNF) into the liver. The primary source of TNF is end toxemia, which is released from the liver and circulates throughout the body (Tracey, 2007). Tumor necrosis factor-alpha is a critical cytokine with different harmful effects, including the production of more inflammatory cytokines with the infiltration of macrophages (Tracey, 2007). The HFD can enhance the oxidative stress, inflammation, and activation of Nuclear Factor kappa Beta-cell (NF-kB) in the rat cerebral cortex, raising the possibility that HFD increases dementia risk (Zhang et al., 2022). Motivation, reward, punishment, energy expenditure, and working memory are all functions of dopamine, which has been recognized as an important neurotransmitter in brain function (Cools, 2008). Increased dietary fat intake has been linked to a decrease in dopamine signaling, which may increase the calorie intake to compensate for this decreased dopamine. Dopamine is a neurotransmitter that influences food intake, particularly pleasing dietary ingredients. However, increased dietary fat intake has been linked to a decrease in dopamine signaling, which may increase the calorie intake to compensate for this decreased dopamine (Vucetic and Reyes, 2010; Hryhorczuk et al., 2016; Joshi et al., 2021). Studies have confirmed that the brain is sensitive to dietary essential fatty acids, and such a diet can make remarkable changes in membrane composition, consequently altering neurons' metabolic

ISSN 2322-4568

> R i

e i

P v

e ft

d :

> a

T3 a

1 c

to h

O 2

2 O

3

0

1 —

G

HH

N A L

A R

T —

C L

E

264

properties. In other words, changes in dietary fat composition could have a significant effect on membrane composition and neuronal functions of the brain (Dyer and Greenwood, 1988; Adermark et al., 2021; Dyall et al., 2022).

The central nervous system consists of several distinct brain areas that control memory and learning processes; however, the hippocampus has a prominent function. The dorsal hippocampus appears to be primarily linked to cognition, while emotion, affect, and stress bind in the ventral hippocampus; this region is unique in that its anatomical activities are divided along the dorsoventral axis (Fanselow and Dong, 2010). Both the dorsal and ventral gyrus of the hippocampus are collectively referred to as the dentate gyrus and are sites of postnatal hippocampal neurogenesis. This process facilitates the maturation of new neurons, which eventually become integrated into the hippocampal circuitry and contribute to its function. The dorsal hippocampus, in particular, plays a crucial role in spatial memory processing (Bannerman et al., 2014; Bortolotto et al., 2014).

There may be a benefit to the Barnes Maze over the Morris Water Maze for subjected rodents which have swimming difficulty because of obesity or other metabolic problems brought on by an HFD (Pitts, 2018). The elevated plus maze test assesses anxiety in lab animals. As a general research instrument, a maze test is typically conducted on rodents for neurobiological anxiety studies and acts as a screening test for potential anxiolytic or anxiogenic substances (Kraeuter et al., 2019). The western diet (rich in fat and sugar) has also been linked to learning, memory (spatial), cognition, and hedonics (Francis and Stevenson, 2013). Spatial memory loss and cell death in the hippocampus can be caused by fat-rich meals (Asadbegi et al., 2017). Moreover, the unbalanced production of reactive oxygen species and the body's antioxidants play a significant role in the neurotoxicity caused by an HFD. When exposed to oxidative stress, cell death occurs due to hydroxyl radical formation, lipid peroxidation, and apoptosis (Ganji et al., 2017; Rozha et al., 2022). Studies have shown that a diet mainly containing saturated fatty acids with trans-fatty acids increases the melatonin hormone secreted from the pineal gland during the dark period and has a vital role in immunity. Daily melatonin administration affects some physiological parameters, including glycemic index, leptin, and dopamine (Al-Azawi et al., 2003). In addition, melatonin decreases lipid levels by increasing the conversion of endogenous cholesterol to bile acids and suppresses cholesterol synthesis and accumulation (Kara and Kara, 2022). Melatonin stimulates the synthesis of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, and glutathione reductase (Sabeeh and Khudair, 2017).

Melatonin N-acetlyl 5methoxytryptamin, isolated for the first time from pineal glands of bovine (Lerner et al., 1958; Venegas et al., 2012), is an endo-neurohormone derived from tryptophan (García-Bernal et al., 2021). The lack of melatonin can lead to various health problems, including neurodegenerative illnesses, circadian rhythm and mood disorders deprivation, diabetes type two, and pain (Comai and Gobbi, 2014). Some health problems, such as obesity, diabetes, hypertension, and respiratory diseases, can be linked to sleep deprivation (Kuvat et al., 2020) since sleep deprivation negatively affects biological and physiological processes (McEwen, 2006; Yin et al., 2017). Melatonin secretion occurs just as sleep propensity since there is a decrease in core body temperature, alertness, and performance (Pandi-Perumal et al., 2008; Borbély et al., 2016). Hippocampal neurons directly respond to melatonin's effects on memory formation (Chang et al., 2021). Melatonin has been shown to have anti-nociceptive, antidepressant, anxiolytic, anti-neophobic, and locomotor activity-regulating effects (Uz et al., 2005; Mantovani et al., 2006; Fenton-Navarro et al., 2021). Melatonin can mediate the effects of mitochondria on physiological processes (Reiter et al., 2014). Melatonin improves the flow of electrons in the inner mitochondrial membrane, which in turn protects the morphology of the cell membrane. It also boosts the activity of antioxidant enzymes, scavenges free radicals, and enhances functional aspects of the cell (García et al., 2020). Improved membrane fluidity, decreased edema, and reduced infiltration of polymorphonuclear cells into damaged tissue are among the factors that result in a decrease in the expression of proinflammatory cytokines. Melatonin achieves this by preventing nuclear factor-kB translocation to the nucleus and binding to DNA, both of which are crucial factors in the inflammatory response (Mayo et al., 2005). Methamphetamine results in an expression reduction of dopamine transporter in the rat hippocampus, which was stopped and reversed by melatonin (Panmak et al., 2021). With this in mind, the current study aimed to examine the detrimental effects of a high-fat diet on animal behaviors and brain processes and to investigate the potential of melatonin to mitigate any negative effects.

MATERIALS AND METHODS

Ethical approval

Animal care and treatment in this study were carried out at the Faculty of Veterinary Medicine, University of Baghdad, Iraq, strictly following the code of ethics for animal experiments (P.G. 201 date 25-1-2023).

Study design

A total of 30 adult male white local rats with an average weight of 160-200 g were housed in special plastic cages (15^70x60 cm) in a room at the animal house of the Veterinary Medicine College, Baghdad University, Iraq. The rats were sustained under controlled conditions for 12 hours of light and 12 hours of darkness at the temperature of 22-25°C

265

and 40% ± 5% relative humidity. The rats were acclimatized for 10 days prior to the trial. For adaptation, food and water were provided ad libitum. The study lasted 8 weeks. The experimental rats were divided randomly into three equal groups (10 rats in each group). The first group was the control group (CC), in which the rats were fed a basal diet throughout the experiment and received an intraperitoneal (IP) injection of normal saline (Table 1). The second group was fed an HFD for 8 weeks with an IP injection of normal saline during the experiment (Table 1). The third group received the HFD plus melatonin (HFD+M), so the rats were fed a saturated HFD for 8 weeks with an IP injection of 10 mg/kg/daily body weight melatonin (Taher and Arrak, 2016; Maher et al., 2020).

Preparation of the high-fat diet

The diet rich in fat used in the current study was made weekly and stored in sealed bags, kept out of light, and stored at 4°C and humidity less than 50% until used in pelleted form or as round. The HFD formulation and composition are shown in Table 1.

Table 1. Diet ingredients in the present study

Ingredient High-fat diet (g/kg diet) Normal diet (g/kg diet)

Corn starch 150 650

Casein 200 200

Tallow fat 400 0

Oil 0 50

Sucrose 40 40

Cellules 50 50

Vitamin mix 10 10

Methionine 3 3

Salt 2 2

Source: Mashmoul et al. (2017).

Tissue collection and homogenization

At the end of the 8-week experiment, all rats from all groups were anesthetized with intramuscular injection of Ketamine (60 mg/kg) and Xylazine, and subsequently decapitated to remove their entire brain. The brain was dissected and divided into the left and right. To conduct the ELISA test, the right part of the brain was put in 1 ml of cold phosphate buffer saline solution containing 0.5 grams of the right part of the brain. Afterwards, the mixture was homogenized using an electrical homogenizer on ice, tissue homogenates were then centrifuged at 5000 rpm for 5 minutes, and an aliquot of the supernatant was isolated to determine TNF-a and dopamine 40 ^l from an aliquot for each parameter. The left part of the brain was kept in plastic containers with formalin (10%) for routine histological examination.

Parameters

Dopamine and TNFa concentration in a male rat brain (ng/L) were measured using ELISA kit (Bioassay Laboratory Technology, Chain). Nervous system impairment was assessed using Barns maze and Elevated plus maze. The Barnes Maze comprises a dry, raised circular platform with many potential escape holes around its perimeter. A secret escape box is concealed behind a single hole. The Barnes labyrinth was effective for testing spatial memory. The typical Barnes maze protocol includes three phases, including habituation, earning (training), and memory. To quantify rat anxiety, Elevated plus maze was used. It is a plus-shaped solid white apparatus with two arms of 84cm long and 10 cm wide. Opposite arms had sides that were 2cm high (open arms), and the sides of the other opposite arms were 17 cm tall (closed arms), elevated above the floor in high 80 cm from the floor.

Histopathological study

Immediately after animal sacrifice, brains from each group were preserved in 10% formalin, and the formalin level was 10:1 of the specimen's volume. The tissues were rinsed in tap water to remove the formalin solution from the samples for three or four hours. The samples underwent various processes to make the tissue suitable for histopathological examination. These steps include dehydration, clearing, embedding, blocking, cutting, and staining (Bancroft et al., 2013).

Statistical analysis

The collected data were analyzed statistically using the Two-way and One-way ANOVA in GraphPad Prism 9.1.0. Data were subjected to a Tukey's post hoc test in case the ANOVA was statistically significant. Results were represented as mean ± standard error, with p value less than 0.05 as statistically significant.

266

RESULTS

The level of dopamine

After 8 weeks of treatment, the obtained data confirmed a statistically significant decrease (p < 0.05) in the dopamine concentration of the HFD group, compared with CC and HFD+M groups (Table 2). However, there was a significant increase in dopamine concentration in CC and HFD+M groups, compared to the HFD (p < 0.05). Melatonin could elevate dopamine influenced by an HFD and increase the concentration of dopamine, when compared with the HFD group.

Brain tissue level of tumor necrosis factor-alpha concentration cytokine (ng/L)

The findings indicated a significant increase in brain TNF-a concentration group fed HFD, compared with CC and HFD+M groups (p < 0.05). Moreover, there was a significant increase in TNF-a brain level in the HFD+M group, compared to the control group (p < 0.05). However, the increment was slight and the value of tumor necrosis factor-alpha concentration (TNF2-a) for the HFD+M group was close to that of the control group. There was a significant decline in TNF-a concentration in the HFD+M (223.9±1.041), compared to the HFD group (p < 0.05, Table 3). As can be seen in Table 4, there was a non-significant difference between the HFD+M group and the control group at the end of the study (p > 0.05). However, there was a significant difference between the HFD and control groups at the end of study (p < 0.05).

Assessment of spatial memory using Barnes maze task

The results indicated that the HFD had a significant negative impact on spatial memory performance (p < 0.05). This was demonstrated by an increased time taken by the HFD group to reach the escape box at 8 weeks (5.533 ± 0.020), compared to both other groups at 8 weeks and the same HFD group at the beginning of the treatment. However, the HFD+M group demonstrated a significantly shorter time to reach the escape box (3.872±0.020), compared to the HFD group at 8 weeks. This suggests that rats fed an HFD may have a deficit in spatial memory.

Determination of anxiety by elevated plus maze

The results of this Elevated Plus maze showed the HFD was more anxious than rats in the HFD+M and CC groups. The HFD rats spent a significantly longer time (p < 0.05) in the close arm (4.525±. 287), compared to the control (2.863 ± 0.157) and HFD+M (3.013 ± 0.147) groups in the same arm. However, the HFD+M group spent significantly less time in close arm than the HFD group (p < 0.05). The HFD rats spent significantly less time (p < 0.05) in the open arm (1.475 ± 0.287), compared to that of the control group (3.138 ± 0.157) and HFD+M groups (2.988 ± 0.147). This means that HFD rats were highly anxious, as they spent a longer time in the close arm, compared with the other groups (Table 5).

Table 2. Effect of high-fat diet and melatonin on dopamine concentration (ng/L) in brain tissue of adult male rats

' ----Groups Time ' ^^^ Control High-fat diet group Melatonin plus a high-fat diet

8 Weeks 11.80 ± 0.23a 2.36 ± 0.11c abT^:_c-______„ ____________■ j______ 6.09 ± 0.19b

Data represented as mean ± standard error mean, n = 10 for each group. abDifferent superscript letters in the same row indicate significant differences

(p < 0.05)

Table 3. Effect of high-fat diet and melatonin on tumor necrosis factor-alpha concentration (ng/L) in brain tissue of adult male rats

r --—^Groups Control Time —__ High-fat diet group Melatonin plus a high-fat diet

8 Weeks 213.7 ± 1.249c 646.1 ± 1.098a 223.9 ± 1.041b

Data represented as mean ± standard error mean, n = 10 for each group; between groups (p < 0.05) abcDifferent superscript letters indicate the significant differences in rows

Table 4. The effect of melatonin and high-fat diet on spatial memory barns maze test

r —-—___Gror Control Time "—-— High-fat diet group Melatonin plus a high-fat diet

Beginning of study 3.765 ± 0.028>a 3.755 ± 0.016Aa 3.783 ± 0.009>

8 Weeks 3.877 ± 0.007> 5.533 ± 0.020Bb 3.872 ± 0.020>

Data represented as mean ± standard error, n = 10 each group; abSmall superscript letters in the same column indicate significant differences between 8 weeks and beginning time (p < 0.05); ABCapital superscript letters in the same row indicate significant differences (p < 0.05).

Table 5. The effect of melatonin and high-fat diet on anxiolytic test by Elevated Plus maze

r --^Gr°ups Control Time —----___ High-fat diet group Melatonin plus a high-fat diet

Open 3.138 ± 0.157Aa Close 2.863 ± 0.157Aa 1.475 ± 0.287>b 4.525 ± 0.287Bb _______ ^n. abT __________________ 2.988 ± 0.147> 3.013 ± 0.147>

ABCapital superscript letters denote the significant differences in the same column (p < 0.05); abLower superscript letters indicate significant differences in the same row (p < 0.05); Data represented as mean ± standard error, n = 10 pre-group.

267

The recent histopathological examination indicated the detrimental effect of a high-fat diet on the brain tissues of rats, and also highlighted the antioxidant and anti-inflammatory properties of melatonin, which played a role in mitigating these effects. In the hippocampus of the CC group, brain sections showed all three layers the molecular layer (ML), the middle layer (pyramidal cell layer, PL), and the inner layer (polymorphic cell layer, PCL). A normal dentate gyrus consists of three layers, including the outer molecular layer, middle granular layer, and inner polymorphic layer. The blood vessels in the molecular and polymorphic layer of the dentate gyrus were normal (Figure 1). Moreover, normal thin meninge, normal brain tissue with normal blood vessels, normal glia cells, astrocytes with oligodendrocytes, and the neuronal cell showed normal triangular perikaryon with prominent central nuclei with apical dendrites (Figures 2 and 3).

Figure 1. The brain tissue of a rat in control group. All layers of the hippocampus contain the outer layer molecular layer (ML), Middle layer pyramidal cell layer (PL), and inner layer polymorphic cell layer (PCL) are shown. There is normal dentate gyrus which contains three layers outer molecular layer, middle granular layer, and inner polymorphic layer. Normal blood vessels in the molecular and polymorphic layer of dentate gyrus. 20X (H&E).

Figure 2. The brain tissue of a rat in control group. The neuronal cell (N) showed normal triangular perikaryon with prominent central nuclei with apical dendrites, and normal glial cell (G) is also seen. 200X (H&E).

268

Figure 3. The brain tissue of a rat in the high-fat diet group. There is disorganization and degenerated pyramidal cells; these cells showed vacuolation (V) in the cytoplasm and pyknotic (condensed) nucleus. Dilation of blood capillaries (BV) and increased numbers of microglia (gliosis, G) in the molecular layer (ML) and polymorphic cell layer (PCL). 50X (H&E).

However, rat brain sections in the HFD group indicated disorganization and degenerated pyramidal cells. These cells showed vacuolation in the cytoplasm and pyknotic (condensed) nucleus, dilation of blood capillaries, and increased numbers of microglia (gliosis in ML and PCL), as in Figure 4. Figure 5 shows a thin pyramidal cell layer in the Cornu Ammonis with degeneration of neurons and V in the last area of cornu Ammonis and dentate gyrus at the brain of the HFD group. In addition, fine capillaries had congestion with cerebral edema in the inner polymorphic layer. In the same group, the histopathological change revealed vacuolation in the granular layer of the dentate gyrus with many glia cells (glia cells in ML and PCL of dentate gyrus), as in Figure 6. Higher magnification of the granular layer of the D indicated the marked vacuolation of the granular cells, which appear swelling, and vacuoles in their cytoplasm and pyknotic nuclei look (Figure 7).

Regarding the brain of HFD rats, the histopathological examination revealed congestion in the blood vessels with marked cerebral edema in which Virchow-Robin space dilated. Many neurological cells appeared shrunken and deeply stained, and infiltration of a high number of glia cells and Astrocytes Astrocytosis (Figure 8). In higher magnification, the neurological cell (neuron) indicated marked central chromatolysis in which the body of the neuron (perikayo) was spherical with nuclei disappearance. Moreover, gliosis and Astrocytosis were detected in the brain tissue (Figure 9). Representative photomicrographs were obtained using 40 x (200x with a factor of a camera, magnification objective). The brain rats in the HFD group indicated gliosis and Astrocytosis with the presence of Oligodendrocytes, marked central chromatolysis in the body of neurons (spherical and disappeared nuclei). Also, fine capillaries were congested in the brain tissue (Figure 10). The microscopic brain examination of rats in the HFD group can be seen in Figure 11. As indicated, there were marked degenerative areas and necrosis of neurons. The neuron showed pale color and disappearance of nuclei with marked aerophagia in the brain tissue. Cerebral edema and congestion of blood vessels were also seen. Moreover, at the same area but at a higher magnification, severe central Chromatolysis of perikaryo of neurons with gliosis and astrocytosis could be noticed (Figure 12). As can be seen in Figure 13, the brain tissue sections also exhibited severe congestion and infiltration of inflammatory cells in the meninges, vacuolation, and aerophagia and marked gliosis and astrocytosis.

According to Figure 14, most neuronal cells (neuron) appeared normal triangle perikaryo with central and prominent nuclei; however, a few of these cells had central chromatolysis with blood vessels. The histopathological section of the hippocampus in rats given melatonin was nearly similar to that of the control. The first area of Cornu Ammonis appears clear and thick, with a high number of pyramidal cells in the middle. There was a normal outer ML; however, the PCL showed few congestions in the fine capillaries. There were normal and high numbers with the normal shape of neurological cells in the last area of Cornu Ammonis, the thick dentate gyrus layer in which there were a high number and proliferation of granular cells with few vacuolations (Figure 15). Moreover, most neurons appeared normal

269

with central nuclei in their perikaryo, but a few neurons underwent chromatolysis in the last area of Cornu Ammonis. There was little vacuolation in the dentate gyrus at the granular layer, mild perivascular edema in the molecular layer, and few glia cells in ML and PCL of the dentate gyrus (Figure 16).

Figure 4. The brain tissue of a rat in the high-fat diet group. The thin pyramidal cell layer in the Crnu Ammonis (CA) with degeneration of neurons (N) and vacuolation (V) in the last area of Cornu Ammonis and dentate gyrus (D) are shown. There is congestion of fine capillaries (C) with cerebral edema (OD) in the inner polymorphic layer. 50X (H&E).

. <» ,. \ • c» a IP • - • fJ

Figure 5. The brain tissue of a rat in the high-fat diet groups. There is vacuolation in the granular layer of the dentate gyrus with the presence of a high number of glia cells (gliosis, G) in the molecular (ML) and polymorphic layer (PCL) of the dentate gyrus (D). 50X (H&E).

270

Figure 6. The brain tissue of a rat in high-fat group. The granular layer of the dentate gyrus shows the marked vacuolation of granular cells (V), which appear to be swelling (S) and vacuoles (V) in their cytoplasm and pyknotic nuclei. 200X (H&E).

Figure 7. The brain tissue of a rat in high-fat diet group. The marked congestion in the blood vessels (BV) with marked cerebral edema (OE) in which there is dilation of Virchow-Robin space. Many neurological cells appeared shrunken and deeply stained (N). Infiltration of many glial cells (gliosis, G) and Astrocytes (Astrocytosis, A). 50X (H&E).

271

Figure 8. The brain tissue of a rat in the high-fat diet group. The neurological cell (neuron) shows marked central chromatolysis (CR) in which the neuron's body (perikaryon) shows spherical nuclei disappearance. There is gliosis (G) and Astrocytosis (A) in the brain tissue. 200X (H&E).

Figure 9. The brain tissue of a rat in high-fat diet group. There is gliosis and Astrocytosis with the presence of Oligodendrocytes (O). Marked central chromatolysis in the body of neurons (CR, spherical in shape and disappeared nucli). There is congestion (C) of fine capillaries in the brain tissue. 200X (H&E).

272

Ulf»

>

*■ I fjT'i—»fl»Tr in ir

mm »f • "Gel»*«SKI

a." itifr .

• »»iTIb • * v

f « TT

. *

& ö

♦ , I

V r / . c ' V

* 91Lr J*Vf | * :

* * ' aI

' • I I

% • ■ t

y .-« _// ^ «Stk / ,1 i« _ «

"»'». 4

, « • k*J

*>♦ - '

>

V ft.

L •

■ %

■■•Ar m №

A

* ll

V f

58

ISr&i' I«

> • ; 2 \

^ J >\ »» •

fj A.* • « fSS

ff

■S^Sja

* t ' | u m' *» » i »»

TraBSKSXFffiacraK^ •• - yv. - «• -A -=',

Figure 10. The brain tissue of a rat in high-fat diet group. Marked degenerative area thin the brain tissue (D) in which there is necrosis of neurons (N), the neuron showed pale in color and disappearance of nuclei with marked neurophagia in the brain tissue. Cerebral edema (OE) and congestion of blood vessels (C) are also seen. 50X (H&E).

Figure 11. The brain tissue of a rat in the high-fat diet group. Severe central chromatolysis (CR)of perikaryon of neurons with gliosis(G) and Astrocytosis(A). 200X (H&E).

273

Figure 12. The brain tissue of a rat in high-fat diet group. Severe congestion and infiltration of inflammatory cells (M) in meninges (meningitis). Vacuolation (V) and neurophagia (N) in the brain tissue and marked gliosis (G) and astrocytosis (A) are noted in this section. 50X (H&E).

Figure 13. The brain tissue of a rat in the high-fat diet plus melatonin group. Few vacuolations in the granular cells (V) of the

dentate gyrus, and most of these cells showed prominent nuclei. Few glia cells (G) in the molecular layer (ML) of the dentate gyrus. 200X (H&E).

274

Figure 14. The brain tissue of a rat in the high-fat diet plus melatonin group. Most neuronal cells (neuron)(N) showed normal triangle perikaryon with central and prominent nuclei, but few of these cells suffer from central chromatolysis (CR). Normal blood capillaries (BV) and few glia cells (G). 200X (H&E).

Figure 15. The brain tissue of a rat in high-fat diet plus melatonin group. The hippocampus showed nearly similar to the control. The first area of Cornu Ammonis (CA) is clear and thick, with a high number of pyramidal cells (PL) in the middle; there is a normal outer molecular layer (ML). But the inner polymorphic layer showed few congestions in the fine capillaries (BV). There are normal and high numbers with the normal shape of neurological cells (N) in the last area of cornu Ammonis. Thick dentate gyrus layer (DG) in which there is a high number and proliferation of granular cells with little vacuolation in it (GC). 20X (H&E).

275

Figure 16. The brain tissue of a rat in the high-fat diet plus melatonin group. Most neurons showed normal with central nuclei in their perikaryon, but few neurons undergo chromatolysis (CR) in the last area of Cornu Ammonis (CA). Few vacuolation (V) at the granular layers of the dentate gyrus, mild perivascular edema (OE) in the molecular layer, and few glia cells (G) in the molecular layer and polymorphic layer (PCL) of the dentate gyrus. 50X (H&E).

DISCUSSION

The obtained findings were inconsistent with a recent study which revealed a dopamine decrease in male and female mice fed HFD, compared to the control group after a day and a week (Wallace et al., 2022). Not only significant effects on dopamine were reported, but fat rats were also shown to have lower levels of dopamine receptor D2 (DRD2) when fed a high-fat or high-sugar diet (Fritz et al., 2018). Moreover, another study indicated that 2 weeks of HFD consumption in adult Sprague Dawley rats induced disrupted dopamine networks, compared to the control group (Barnes et al., 2022). This result agrees with that of Han et al. (2021), showing that HFD-exposed mice had significantly higher midbrain DA and DRD2 protein levels compared to the control group. During the 8 weeks of HFD, obese rats showed 42% lower striatal DRD2 density and 30% lower total dopamine transporter (DAT) expression (Sharma and Fulton, 2013). These results agreed with a previous study that indicated lower striatal dopamine 2-receptor density, lower total dopamine transportal expression, and lower in vitro and in vivo dopamine transport function after an 8-week HDF exposure due to the positive correlation between circulating leptin and stress-induced dopamine release (Narayanaswami et al., 2013). The literature reviewed here suggests that leptin acts as a regulator of neuronal function and may provide an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli. When leptin is present, messages are sent to the brain's reward centers, where the dopamine system lowers the value of foods as a reward (Burghardt et al., 2012; Yeung and Tadi, 2020).

A high-fat, low-carbohydrate diet disrupts dopamine function linked to changes in brain neuroactivity due to dopamine dysregulation. Other behavioral-related neurochemical pathways may be impacted (Han et al., 2021). After 5 months of feed exposure, neurochemical studies showed that HFD-exposed mice had significantly greater DA and DRD2 protein levels in the midbrain, compared to the control group. They suggest that the effects of HFD on the C57BL/6J mice strain become apparent by the third month of dietary exposure (Han et al., 2021). Dopamine neurotransmission impairment has been linked to metabolic abnormalities produced by saturated fat (Serafine et al., 2016; Fordahl and Jones, 2017; Narayanaswami et al., 2013; Barnes et al., 2022).

However, it was indicated that dopamine levels were reduced in the melatonin groups, compared to the control group in a previous study (Lin et al., 2008). Previous studies have revealed that melatonin inhibits dopamine expression and serves as an antioxidant to prevent nigrostriatal neurodegeneration and alpha-syncline aggregation (Zisapel, 2001). Melatonin upregulation of the D2 receptor reduces the neuronal loss and downregulation of the dopamine transporter

276

(Lin et al., 2008; Deng et al., 2015). Another investigation revealed that the group which received Acrylamide presented decreasing in neurotransmitters, such as dopamine. In contrast, dopamine was higher in the group that received Acrylamide and melatonin but still lower than in the control group as the melatonin protected the DNA damage and antiinflammatory effect (Edres et al., 2021). Another study showed the IP therapy of 10 mg/kg body weight melatonin could lessen oxidative damage by boosting the activity of antioxidant enzymes, reducing lipid peroxidation and inflammation, and enhancing histopathological changes in the brain tissue of rats with pinealectomy (Bicer et al., 2022). Finally, melatonin may suppress neural nitric oxide synthase activity, leading to a decrease in NO and peroxynitrite formation (which play a critical role in the losses of dopaminergic neurons. This may inhibit the activity of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis (Teixeira et al., 2003; Ahmed et al., 2010; Pandi-Perumal et al., 2013).

A powerful pro-inflammatory cytokine called TNF is essential for starting and maintaining the inflammatory response. Elevated levels of TNF-a have been documented in several neurodegenerative disorders and insults with the potential to affect the Central Nervous System; for neurodegenerative diseases linked to neuroinflammation, controlling TNF-signaling may be advantageous (Frankola et al., 2011). The current experiment showed that the brain level of TNF -a cytokine was significantly higher in the HFD group, compared to other groups. These findings support the peripheral pro-inflammatory effects of inflammation of the used obesogenic diet. The current results of TNF-a, in parallel with many previous studies, revealed that the plasma biomarkers, TNF-a, and brain hippocampal significantly increased in HFD group rats, compared with the normal control rats (Xu et al., 2019; Ebrahim et al., 2021; Hsu et al., 2021). Further, the results of the study were similar to those of a previous study that examined HFD and inflammation. In rats who were given HFD for many weeks compared with those who were given a normal diet for the same period, TNF-alpha levels in the brain and different serum parameters were elevated (Spagnuolo et al., 2015).

The possible immunological mechanism that led to the elevation of TNFa has been explained in different studies. The Saturated fatty acids and lipopolysaccharides operate as agonists for the toll-like receptor 4 (TLR4), which it can bind to and activate. This causes nuclear factor kappa B (factor NF-B), leading to pro-inflammatory synthesis of cytokine, such as TNF-a (Rogero and Calder, 2018). Neuronal stress in response to HFD is associated with increased NF-kB signaling (Vykhovanets et al., 2011). Consuming an HFD raises oxidative stress and decreases mitochondrial activity in the brain (Tan and Norhaizan, 2019; Langley et al., 2020). Astrocytes and microglia produce substantial amounts of TNF in pathological settings; this de novo synthesis is a crucial part of the so-called neuroinflammatory response linked to several neurological disorders (Montgomery and Bowers, 2012). Although astrocytes and neurons can generate TNF-a, the microglia are believed to be the primary source of this cytokine during neuroinflammation (Chung and Benveniste, 1990; Welser-Alves and Milner, 2013). The cytokine interferon-gamma (IFN-a) is a strong inducer of TNF production in microglia (Mangano et al., 2012; Olmos and Llado, 2014).

In the current study, melatonin administration restored the normal level of TNF-a in HFD+M. This agrees with previous investigations in which 10 mg/kg of melatonin was administrated for 20 days. The results indicated that administration of melatonin led to significant lowering levels of IL-ip, NF-kB, and TNF-a as the melatonin exerts antiinflammatory influence by reducing TNF-a, interleukin-ip and iNOS, markers in diabetes mellitus (DM) induced animals (de Melo et al., 2020). However, in a recent study, it was reported that the administration rats with melatonin at the dosage of 500 ^g/kg/day in diabetes mellitus DM rats for 6 weeks resulted in significant of the liver and adipose tissues TNF and NF-kB lower than in the control animals (Yapislar et al., 2022). Moreover, it has been demonstrated that melatonin inhibits the synthesis of pro-inflammatory cytokines, such as TNF-a. Rats had significantly lower levels of the transcription factor NF-kB, which is crucial for innate immunity and mediates the production of the pro-inflammatory cytokines TNF-a (Somade et al., 2019; Brazao et al., 2022). On the other hand, another study showed the effect of melatonin on ischemic brain injury in the apoptotic response and inflammation in aged rats. It was found that the animals given melatonin starting 24 hours before surgery and continuing for the first 7 days after an ischemic stroke led to oxidative stress, blood-brain barrier dysfunction, post-ischemic inflammation, and microvascular injury. Moreover, there was a significant decline in tumor TNF-a and interleukin-1 beta (IL-1 beta) levels (Rancan et al., 2018). Prior research has shown that melatonin can prevent the transcriptional activation of IL1 and TNF-a by blocking NF-kB binding to DNA (Chuang et al., 1996; Li et al., 2005; Farid et al., 2022). In addition, melatonin therapy attenuates the inflammatory signals triggered by insulin resistance/hyperinsulinemia, reducing adipose/hepatic inflammation (Obayemi et al., 2021).

The recorded findings agreed with a previous study that revealed that a diet rich in fat drastically lowered spatial working memory performance in the Y-maze test (Ajayi et al., 2021). Moreover, feeding rats with a diet rich in fat for two months impaired their learning ability, and rats took longer and traveled a longer distance compared with the control in the Morris Water Maze task (Sepehri et al., 2019). There is still much mystery about how a high-fat, low-carbohydrate diet can impair mental acuity. Multiple studies have shown HFD to increase oxidative stress and free radical generation, leading to lipid peroxidation and changes in the blood-brain barrier's structural components (Reiter et al., 2014; Alzoubi et al., 2017; Alzoubi et al., 2018). Moreover, Abdulwahid (2019) stated that HFD impaired hippocampal neural function by impairment of inhibitory neurotransmitters. Furthermore, the activation of astrocytes might be a remarkable indication of inflammation in the hippocampus (Abdulwahid, 2019). Neuronal damage markers, such as serotonin, dopamine, and

277

glutamate were significantly altered in the brains of HFD rats, which may explain the resulting apoptosis of hippocampus cells and cognitive impairment (Labban et al., 2020; Parkington et al., 2020). it was suggested that melatonin improved spatial learning and memory by reducing isoflurane-induced endoplasmic reticulum stress and neuroapoptosis in the hippocampus and serum levels of neuroinflammatory markers (Fang et al., 2022). A decrease in the inflammatory response in pro-inflammatory cytokines, such as interleukin-1 (IL-1), and tumor necrosis factor Alfa (TNF-a), and an increase in anti-inflammatory cytokines like IL-4 have been observed in an animal study where exogenous melatonin was administered before acute conditions (Carrasco et al., 2013). In addition, melatonin reduces the formation of high amounts of prostanoids and leukotrienes, and other mediators of the inflammatory process, such as chemokines and adhesion molecules, by inhibiting the expression of cyclooxygenase and inducible nitric oxide synthase (iNOS, Liu et al., 2017). To measure the anxiety-like behavior in experimental animals, Elevated plus maze (EPM) was used. The current EPM findings agreed with previous studies, which reported that an HFD impairs assessed anxiety-like as well as working memory behaviors by decreased open arm time in the EPM, and increased movement and rest episodes and decreased rearing in the open field test (Hu et al., 2017; Holl et al., 2018; Deal et al., 2020). Previous studies on the cognitive deficits and anxiety-like behavior in rodents fed an HFD indicated that indoleamine 2,3-dioxygenase (IDO) activity and pro-inflammatory cytokines were involved in the proposed mechanism (André et al., 2014; Parkington et al., 2019). On the contrary, Kaczmarczyk et al. (2013) reported that HFD rapidly impacts dopamine metabolism in the brain, appearing to trigger anxiety-like behaviors and learning/memory impairments. In the reduction of the ratio of reduced glutathione GSH: oxidized glutathione GSSG, by elevation of cytosolic reactive oxygen species, anxiety-like behaviors in mice can be observed (Llorente-Folch et al., 2013). Finally, in rat research, it has been demonstrated that amphetamine withdrawal causes depression and anxiety-like behavior associated with DA dysregulation. In the hippocampus and amygdala, the dopamine D1 and D2 receptors are associated with anxiety-related behaviors (Svingos et al., 2001; Lee et al., 2018).

In a sporadic rat model of Alzheimer's, melatonin administration during the disease's active stage of progression decreased amyloid deposition in the hippocampus (P1-42 and pi-40) and frontal cortex (P1-42), decreased degenerative changes in the hippocampus, prevented mitochondrial dysfunction, and postponed anxiety and cognitive decline (Rudnitskaya et al., 2015). Prolonged melatonin use prevents neurodegeneration in rat's hippocampus by reducing hyperphosphorylation and Ap mediated memory impairments following intracerebroventricular Api-42-injection (Ali and Kim, 2015). After intracerebroventricular injections of soluble A1-42, it has also been found that melatonin enhances spatial memory, decreases astrogliosis in the rat hippocampus, and decreases synaptic dysfunction (Zhang et al., 2016). In a sporadic rat model of Alzheimer's disease, it has been discovered that long-term oral melatonin administration and maintains the neuronal and glial structure increases hippocampus synaptic development (Stefanova et al., 2015). Previous studies have revealed that feeding heavily on fat and carbohydrates can increase blood-brain barrier permeability and impair cognition (Davidson et al., 2013). These results confirm that rats administered HFD have lower hippocampus plasticity. Additionally, hippocampus volume shrinks, and the hippocampus volume will inevitably decline due to neuronal death (Cherbuin et al., 2015).

An electron microscopy analysis revealed that rats fed an HFD had degenerative neurons, swallowed mitochondria, expanded endoplasmic reticulum cisterns, and increased lysosomes and vacuoles (Alkan et al., 2021). Similar to previous studies, inflammation caused by fatness leads to various disorders and affects the nervous system. In the CNS, mild cognitive impairment can be attributed to obesity-induced altered hippocampal structure and function (D O'Brien et al., 2017).

Rats on the HFD displayed decreased mRNA expression of the blood-brain barrier capillary system's tight junction proteins, Claudin-5 and Claudin-12. The claudins, among the tight junction proteins, are thought to be the main proteins that create the tight junction features of the endothelial cells and are significant in permeability restriction (Wolburg and Lippoldt, 2002). The HFD was also connected to increased sodium fluorescein (NaFl) permeability from the vasculature to the hippocampus region, which is consistent with the lower production of these proteins (Kanoski et al., 2010). Accordingly, such a diet can alter the brain's internal environment by disrupting the function of the blood-CSF and blood-brain barriers. In conjunction with the hippocampus' apparent vulnerability to increased NaFl permeability, behavioral findings imply that this brain area is more susceptible to the neurotoxic effects of saturated fats and refined carbohydrates on blood brain barrier permeability and cognitive function (Hargrave, 2014; Clasen et al., 2020). By making contact with the endothelial basal lamina, astrocytes control leptin's capacity to penetrate the blood -brain barriers (Hsuchou et al., 2009). According to the previous study, reactive gliosis alters the production and function of these connexins proteins in astrocytes, particularly via opening the connexins hemichannel (Giaume et al., 2021). Certain circumstances, such as reduced pH, oxidative stress, as well as inflammation brought on by injuries, may cause the hemichannel to open (Turovsky et al., 2020). In addition, gliotic astrocytes may directly contribute to tissue injury through local proinflammatory signals. Similar to microglial activation, astrogliosis is triggered by an HFD in mice. This gliosis can be produced by several factors, including the release of nitric oxide (NO, Gzielo et al., 2017). Fat and cholesterol-rich diets are a known risk factor for cognitive decline due to their effects on hippocampus-dependent

278

memory, blood-brain barrier dysfunction, and hippocampal neurogenesis (Lopez-Taboada et al., 2020). It is worth mentioning that the changes occurring in the brain tissue are due to oxidative stress, changes in the mitochondria, and inflammation evident in the microscopic examination through the increase of cells that show inflammation. The majority of the cited research revealed that the effects of insulin on the tissues lead to alterations, which was supported by biochemical investigation through the brain tissue by TNF examination. A previous study revealed Lipid peroxidation reduced after the melatonin infusion, most notably in the brain. An increase in antioxidants, such as GSH-Px activity was also observed after melatonin treatment. This means that melatonin increases the levels of the antioxidative enzyme GSH-Px and removes free radicals (Bayda§ et al., 2001). Melatonin inhibited lipid peroxidation in the mitochondria and the cytoplasm in a different experiment that looked at its capacity to prevent oxidative damage in brain tissue and decrease antioxidative enzyme activity in brain tissue (Shen et al., 2002). Another recent study by Bicer et al. (2022) about the neuroprotective of melatonin gains brain damage so melatonin increased the activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) and improved brain total antioxidant status (TAS) and suppressed lipid peroxidation, inflammatory pathways, and apoptosis. Treatment with melatonin considerably improved the histological features in the hippocampus, cortex, and cerebellar region, which included vacuolation, inflammatory cells, and pyknotic cells (Sarena et al., 2022). Moreover, melatonin applied before radiotherapy protects against early-period radiotherapy-induced brain damage (Aras et al., 2021). Thus, results indicate that melatonin therapy could reduce reactive gliosis. Due to its great efficacy, low toxicity, and ability to cross the blood-brain barrier, it had a neuroprotective impact that reduced cell death and reactive astrogliosis (Alonso-Alconada et al., 2012). The result agreed with a recent study that melatonin protects memory, oxidative stress, and inflammation when dopamine decreases (Amin et al., 2021). Some suggest that melatonin could inhibit the intrinsic pathway of apoptosis to prevent neurodegenerative diseases (de Lima et al., 2005; Tuzcu and Baydas, 2006; Ferreira et al., 2010). This confirms the role of melatonin in pathophysiological mechanisms, such as edema in the central nervous system and peripheral organs (Xu et al., 2017). In a similar study on histopathological examination, melatonin significantly reduced the rates of necrosis, neuronal degeneration, and edema (Erol et al., 2004). The ability of melatonin to stop neuroinflammation caused by a diet rich in fat and heavy sugar in an HFD-T2DM rat model by restoring pancreatic function, reducing adipose tissue mass, and easing dyslipidemia. This will decrease systemic inflammation, eventually stopping neuroinflammation by reducing oxidative stress in the brain and stopping the expression of iNOS (Maher et al., 2020). These results conclude that melatonin's antioxidant activities improve the brain tissues, the neuroprotective ability of melatonin, and the daily administration of 10 mg/kg /body weight of melatonin. These results agreed with a previous study (Favrais et al., 2021), which indicated that the IP injection of melatonin (5 mg/kg/daily) had promising neuroprotective effects due to its antioxidant, anti-inflammatory, and anti-apoptotic properties.

CONCLUSION

Feeding animals with high-fat diets impaired brain neurotransmitters and induced pro-inflammatory changes, as well as affected learning ability and memory by changing the structure of neural tissue. Injection of melatonin at a dose of 10 mg/kg/daily can repair the harmful effect of HFD and restores the normal histological structure of the brain, and biochemistry function, such as dopamine. Future studies are suggested to investigate the effect of different doses of melatonin and its injection time for assessing memory and cognition using Open field test, forced swim test, and Radial arm maze.

DECLARATIONS

Acknowledgments

The authors wished to thank Dr. Khaleel Kzar of the Faculty of Veterinary Medicine, University of Al-Qadisiyah, Iraq, for his assistance in reading the histopathological sections. The authors would like to thank College of Veterinary Medicine, University of Baghdad, for allowing the researchers to conduct the research and use the resources.

Funding

The work received no financial assistance.

Authors' contributions

Dr. Ammar A. Abdulwahid conceptualized the idea and developed an experiment to conduct the laboratory work. Ahmed Raheem Rayshan, Ammar Ahmed Abdulwahid and Alyaa Abdulhussein Alsaedi analyzed data and contributed to the drafting, editing, and production of the final draft. All authors checked and approved the final version of the manuscript.

Competing interests

The authors declare that they have no conflict of interest.

279

Ethical consideration

Ethical issues (including plagiarism, consent to publish, misconduct, data fabrication and/or falsification, double publication and/or submission, and redundancy) have been checked by all the authors.

Availability of data and materials

The data presented in this study are available on request from the corresponding author.

REFERENCES

Abbott KN, Arnott CK, Westbrook RF, and Tran DM (2019). The effect of high fat, high sugar, and combined high fat-high sugar diets on spatial learning and memory in rodents: A meta-analysis. Neuroscience & Biobehavioral Reviews, 107: 399-421. DOI: https://www.doi.org/10.1016/j.neubiorev.2019.08.010

Abdulwahid AA (2019). Maternal obesity-induced hyperactivity in the hippocampus: Adverse impacts on long term brain function. Doctoral Dissertation. Monash University, Australia.

Adermark L, Gutierrez S, Lagström O, Hammarlund M, Licheri V, and Johansson ME (2021). Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition. Psychoneuroendocrinology, 126: 105143. DOI:

https://www.doi.org/10.1016/j.psyneuen.2021.105143

Ahmed HH, Elmegeed GA, el-Sayed SM, Abd-Elhalim MM, Shousha WG, and Shafic RW (2010). Potent neuroprotective role of novel melatonin derivatives for management of central neuropathy induced by acrylamide in rats. European Journal of Medicinal Chemistry, 45(11): 5452-5459. DOI: https://www.doi.org/10.1016/j.ejmech.2010.09.017

Ajayi AM, John KA, Emmanuel IB, Chidebe EO, and Adedapo AD (2021). High-fat diet-induced memory impairment and anxiety-like behavior in rats attenuated by peel extract of Ananas comosus fruit via atheroprotective, antioxidant and anti-inflammatory actions. Metabolism Open, 9: 100077. DOI: https://www.doi.org/10.1016/j.metop.2021.100077 Al-Azawi TSS, Injidi MH, Rhadi AKJ, and Habib AA (2003). The role of melatonin in maintenance of immunological internal environment. The Iraqi Journal of Veterinary Medicine, 27(1): 208-215. DOI: https://www.doi.org/10.30539/ijvm.v27i1.1111

Ali T and Kim MO (2015). Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI

3/Akt/GS k3ß pathway in the mouse hippocampus. Journal of Pineal Research, 59(1): 47-59. DOI: https://www.doi .org/10.1111/jpi. 12238 Alkan I, Altunkaynak BZ, Gültekin Gl, and Bayçu C (2021). Hippocampal neural cell loss in high-fat diet-induced obese rats-exploring the protein networks, ultrastructure, biochemical and bioinformatical markers. Journal of Chemical Neuroanatomy, 114: 101947. DOI: https://www.doi.org/10.1016/j.jchemneu.2021.101947

Alonso-Alconada D, Alvarez A, Lacalle J, and Hilario E (2012). Histological study of the protective effect of melatonin on neural cells after neonatal hypoxia-ischemia. Histology and Histopathology, 27(6): 771-783. DOI: https://www.doi.org/10.14670/HH-27.771

Alzoubi KH, Mayyas FA, Mahafzah R and Khabour OF (2018). Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress. Behavioural Brain Research, 336: 93-98. DOI: https://www.doi.org/10.1016/j.bbr.2017.08.047

Alzoubi KH, Rababa'h AM, Owaisi A, and Khabour OF (2017). L-carnitine prevents memory impairment induced by chronic REM-sleep deprivation.

Brain Research Bulletin, 131: 176-182. DOI: https://www.doi.org/10.1016/j.brainresbull.2017.04.004 Amin SN, Sharawy N, El Tablawy N, Elberry DA, Youssef MF, Abdelhady EG, Rashed LA, and Hassan SS (2021). Melatonin-pretreated mesenchymal stem cells improved cognition in a diabetic murine model. Frontiers in Physiology, 12: 628107. DOI: https://www.doi.org/10.3389/fphys.2021.628107

André C, Dinel AL, Ferreira G, Layé S, and Castanon N (2014). Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: Focus on brain indoleamine 2,3 dioxygenase activation. Brain, Behavior, and Immunity, 41: 10-21. DOI: https://www.doi.org/10.1016/j.bbi.2014.03.012 Aras S, Efendioglu M, Wulamujiang A, Ozkanli SS, Keleç MS, and Tanzer lO (2021). Radioprotective effect of melatonin against radiotherapy-induced cerebral cortex and cerebellum damage in rat. International Journal of Radiation Biology, 97(3): 348-355. DOI: https://www.doi.org/10.1080/09553002.2021.1864047

Asadbegi M, Yaghmaei P, Salehi I, Komaki A, and Ebrahim-Habibi A (2017). Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet-fed rats. Metabolic Brain Disease, 32(3): 827-839. DOI: https://www.doi .org/10.1007/s11011-017-9960-0 Bancroft JD, Layton C, and Suvarna SK (2013). Bancroft's theory and practice of histological techniques, 7th Edition. Elsevier Limited., Chrchill Livingstone Elsevier.

Bannerman DM, Sprengel R Sanderson DJ, McHugh SB, Rawlins JNP, Monyer H, and Seeburg PH (2014). Hippocampal synaptic plasticity, spatial memory and anxiety. Nature Reviews Neuroscience, 15(3): 181-192. DOI: https://www.doi.org/10.1038/nrn3677

Barnes CN, Wallace CW, Jacobowitz BS, and Fordahl SC (2022). Reduced phasic dopamine release and slowed dopamine uptake occur in the nucleus accumbens after a diet high in saturated but not unsaturated fat. Nutritional Neuroscience, 25(1): 33-45. DOI: https://www.doi.org/10.1080/1028415X.2019.1707421

Baydaç G, Erçel E, Canatan H, Dönder E, and Akyol A (2001). Effect of melatonin on oxidative status of rat brain, liver and kidney tissues under

constant light exposure. Cell Biochemistry and Function, 19(1): 37-41. DOI: https://www.doi.org/10.1002/cbf.897 PMid:11223869 Bicer Y, Elbe H, Karayakali M, Yigitturk G, Yilmaz U, Cengil O, Al Gburi MRA, and Altinoz E (2022). Neuroprotection by melatonin against acrylamide-induced brain damage in pinealectomized rats. Journal of Chemical Neuroanatomy, 125: 102143. DOI: https://www.doi.org/10.1016/j.jchemneu.2022.102143

Borbély AA, Daan S, Wirz-Justice A, and Deboer T (2016). The two-process model of sleep regulation: A reappraisal. Journal of Sleep Research, 25(2): 131-143. DOI: https://www.doi.org/10.1111/jsr.12371

Bortolotto V, Cuccurazzu B, Canonico PL, and Grilli M (2014). NF-B mediated regulation of adult hippocampal neurogenesis: Relevance to mood disorders and antidepressant activity. BioMed Research International, 2014: 612798. DOI: https://www.doi.org/10.1155/2014/612798

Brazäo V, Colato RP, Santello FH, Duarte A, Goulart A, Sampaio PA, Pacheco Silva CB, Tirapelli CR, Costa RM, Tostes RC et al. (2022). Melatonin regulates antioxidant defense and inflammatory response by activating Nrf2-dependent mechanisms and inhibiting NFkappaB expression in middle-aged T. cruzi infected rats. Experimental Gerontology, 167: 111895. DOI: https://www.doi.org/10.1016/j .exger.2022.111895 Burghardt PR, Love TM, Stohler CS, Hodgkinson C, Shen PH, Enoch MA, Goldman D, and Zubieta JK (2012). Leptin regulates dopamine responses to sustained stress in humans. Journal of Neuroscience, 32(44): 15369-15376. DOI: https://www.doi.org/10.1523/JNEUROSCI.2521-12.2012

280

Carrasco C, Marchena AM, Holguín-Arévalo MS, Martín-Partido G, Rodríguez AB, Paredes SD, and Pariente JA (2013). Anti-inflammatory effects of melatonin in a rat model of caerulein-induced acute pancreatitis. Cell Biochemistry and Function, 31(7): 585-590. DOI: https://www.doi .org/10.1002/cbf.2942

Chang HM, Lin HC, Cheng HL, Liao CK, Tseng TJ, Renn TY, Lan CT, and Chen LY (2021). Melatonin successfully rescues the hippocampal molecular machinery and enhances anti-oxidative activity following early-life sleep deprivation injury. Antioxidants, 10(5): 774. https://www.doi.org/10.3390/antiox10050774

Cherbuin N, Sargent-Cox K, Fraser M, Sachdev P, and Anstey KJ (2015). Being overweight is associated with hippocampal atrophy: The PATH through life study. International Journal of Obesity, 39(10): 1509-1514. DOI: https://www.doi.org/10.1038/ijo.2015.106

Chuang JI, Mohan N, Meltz ML, and Reiter RJ (1996). Effect of melatonin on nf-Kb dna-binding activity in the rat spleen. Cell Biology International, 20(10): 687-692. DOI: https://www.doi.org/10.1006/cbir.1996.0091

Chung IY and Benveniste EN (1990). Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. The Journal of Immunology, 144(8): 2999-3007. DOI: https://www.doi.org/10.4049/jimmunol.144.8.2999

Clasen MM, Riley AL, and Davidson TL (2020). Hippocampal-dependent inhibitory learning and memory processes in the control of eating and drug taking. Current Pharmaceutical Design, 26(20): 2334-2352. DOI: https://www.doi.org/10.2174/1381612826666200206091447

Comai S and Gobbi G (2014). CCNP award paper: Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: A novel target in psychopharmacology. Journal of Psychiatry and Neuroscience, 39(1): 6-21. DOI: https://www.doi.org/10.1503/jpn.130009

Cools R (2008). Role of dopamine in the motivational and cognitive control of behavior. The Neuroscientist, 14(4): 381-395. DOI: https://www.doi.org/10.1177/1073858408317009

D O'Brien P, Hinder LM, Callaghan BC, and Feldman EL (2017). Neurological consequences of obesity. The Lancet Neurology, 16(6): 465-477. DOI: https://www.doi .org/10.1016/S1474-4422( 17)30084-4

Davidson TL, Hargrave SL, Swithers SE, Sample CH, Fu X, Kinzig KP, and Zheng W (2013). Inter-relationships among diet, obesity and hippocampal-dependent cognitive function. Neuroscience, 253: 110-122. DOI: https://www.doi.org/10.1016/j .neuroscience.2013.08.044

de Lima E, Soares Jr JM, Garrido YDCS, Valente SG, Priel MR, Baracat EC, Cavalheiro EA, da Graja Naffah-Mazzacoratti M, and Amado D (2005). Effects of pinealectomy and the treatment with melatonin on the temporal lobe epilepsy in rats. Brain Research, 1043(1-2): 24-31. DOI: https://www.doi.org/10.1016/j.brainres.2005.02.027

de Melo IMF, Ferreira CGM, da Silva Souza EHL, Almeida LL, de Sá FB, Neto CJCL, de Castro MVP, Teixeira VW, and Teixeira ÁAC (2020). Melatonin regulates the expression of inflammatory cytokines, VEGF and apoptosis in diabetic retinopathy in rats. Chemico-Biological Interactions, 327: 109183. DOI: https://www.doi.org/10.1016/j.cbi.2020.109183

Deal AW, Seshie O, Lenzo A, Cooper N, Ozimek N, and Solberg Woods LC (2020). High-fat diet negatively impacts both metabolic and behavioral health in outbred heterogeneous stock rats. Physiological Genomics, 52(9): 379-390. DOI: https://www.doi .org/10.1152/physiolgenomics.00018.2020

Deng Y, Jiao C, Mi C, Xu B, Li Y, Wang F, Liu W, and Xu Z (2015). Melatonin inhibits manganese-induced motor dysfunction and neuronal loss in mice: Involvement of oxidative stress and dopaminergic neurodegeneration. Molecular Neurobiology, 51(1): 68-88. DOI: https://www.doi .org/10.1007/s12035-014-8789-3

Dyall SC, Balas L, Bazan NG, Brenna JT, Chiang N, da Costa Souza F, Dalli J, Durand T, Galano JM, Lein PJ et al. (2022). Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions. Progress in Lipid Research, 86: 101165. DOI: https://www.doi.org/10.1016/j.plipres.2022.101165

Dyer JR and Greenwood CE (1988). Evidence for altered methionine methyl-group utilization in the diabetic rat's brain. Neurochemical Research, 13(6): 517-523. DOI: https://www.doi.org/10.1007/BF00973290

Ebrahim HA, El-Gamal R, and Sherif RN (2021). Intermittent fasting attenuates high-fat diet-induced cerebellar changes in rats: Involvement of TNF-a, autophagy, and oxidative stress. Cells Tissues Organs, 210(5-6): 351-367. DOI: https://www.doi.org/10.1159/000519088

Edres HA, Taha NM, Lebda MA, and Elfeky MS (2021). The potential neuroprotective effect of allicin and melatonin in acrylamide-induced brain damage in rats. Environmental Science and Pollution Research, 28(41): 58768-58780. DOI: https://www.doi.org/10.1007/s11356-021-14800-x

Erol FS, Topsakal C, Ozveren MF, Kaplan M, Ilhan N, Ozercan IH, and Yildiz OG (2004). Protective effects of melatonin and vitamin E in brain damage due to gamma radiation. Neurosurgical Review, 27(1): 65-69. DOI: https://www.doi.org/10.1007/s10143-003-0291-8

Fang X, Han Q, Li S, and Luo A (2022). Melatonin attenuates spatial learning and memory dysfunction in developing rats by suppressing isoflurane-induced endoplasmic reticulum stress via the SIRT1/Mfn2/PERK signaling pathway. Heliyon, 8(9): e10326. DOI: https://www.doi.org/10.1016/j.heliyon.2022.e10326

Fanselow MS and Dong HW (2010). Are the dorsal and ventral hippocampus functionally distinct structures?. Neuron, 65(1): 7-19. DOI: https://www. doi.org/10.1016/j .neuron.2009.11.031

Farid A, Moussa P, Youssef M, Haytham M, Shamy A, and Safwat G (2022). Melatonin relieves diabetic complications and regenerates pancreatic beta cells by the reduction in NF-kB expression in streptozotocin induced diabetic rats. Saudi Journal of Biological Sciences, 29(7): 103313. DOI: https://www.doi.org/10.1016/j.sjbs.2022.103313

Favrais G, Saliba E, Savary L, Bodard S, Gulhan Z, Gressens P, and Chalon S (2021). Partial protective effects of melatonin on developing brain in a rat model of chorioamnionitis. Scientific Reports, 11(1): 22167. DOI: https://www.doi.org/10.1038/s41598-021-01746-w

Fenton-Navarro B, Ríos DG, Torner L, Letechipía-Vallejo G, and Cervantes M (2021). Melatonin decreases circulating levels of galectin-3 and cytokines, motor activity, and anxiety following acute global cerebral ischemia in male rats. Archives of Medical Research, 52(5): 505-513. DOI: https://www.doi.org/10.1016/j.arcmed.2021.01.009

Ferreira CDS, Maganhin CC, Simoes RDS, Girao MJBC, Baracat EC, and Soares-Jr JM (2010). Melatonina: Modulador de morte cellular [Melatonin: Cell death modulator]. Revista da Associajao Médica Brasileira, 56(6): 715-718. DOI: https://www.doi.org/10.1590/S0104-42302010000600024

Fordahl SC and Jones SR (2017). High-fat-diet-induced deficits in dopamine terminal function are reversed by restoring insulin signaling. ACS Chemical Neuroscience, 8: 290-299. DOI: https://www.doi.org/10.1021/acschemneuro.6b00308

Francis H and Stevenson R (2013). The longer-term impacts of Western diet on human cognition and the brain. Appetite, 63: 119-128. DOI: https://www.doi.org/10.1016/j.appet.2012.12.018 PMid:23291218

Frankola K, Greig NH, Luo W, and Tweedie D (2011). Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS & Neurological Disorders-Drug Targets, 10(3): 391-403. DOI: https://www.doi.org/10.2174/187152711794653751

Fritz BM, Muñoz B, Yin F, Bauchle C, and Atwood BK (2018). A high-fat, high-sugar Western diet alters dorsal striatal glutamate, opioid, and dopamine transmission in mice. Neuroscience, 372: 1-15. DOI: https://www.doi.org/10.1016/j.neuroscience.2017.12.036

Ganji A, Salehi I, Sarihi A, Shahidi S, and Komaki A (2017). Effects of Hypericum scabrum extract on anxiety and oxidative stress biomarkers in rats fed a long-term high-fat diet. Metabolic Brain Disease, 32(2): 503-511. DOI: https://www.doi.org/10.1007/s11011-016-9940-9

281

García S, Giménez VMM, Marón FJM, Reiter RJ, and Manucha W (2020). Melatonin and cannabinoids: Mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases. Histology and Histopathology, 35(8): 789-800. DOI: https://www.doi.org/10.14670/hh-18-212

García-Bernal D, López-García S, Sanz JL, Guerrero-Gironés J, García-Navarro EM, Moraleda JM, Forner L, and Rodríguez-Lozano FJ (2021). Melatonin treatment alters biological and immunomodulatory properties of human dental pulp mesenchymal stem cells via augmented transforming growth factor beta secretion. Journal of Endodontics, 47(3): 424-435. DOI: https://www.doi.org/10.1016/j.joen.2020.12.008

Giaume C, Naus CC, Saez JC, and Leybaert L (2021). Glial connexins and pannexins in the healthy and diseased brain. Physiological Reviews, 101(1):

93-145. DOI: https://www.doi.org/10.1152/physrev.00043.2018 Gzielo K, Kielbinski M, Ploszaj J, Janeczko K, Gazdzinski SP, and Setkowicz Z (2017). Long-term consumption of high-fat diet in rats: Effects on microglial and astrocytic morphology and neuronal nitric oxide synthase expression. Cellular and Molecular Neurobiology, 37(5): 783-789. DOI: https://www.doi .org/10.1007/s10571-016-0417-5

Han J, Nepal P, Odelade A, Freely FD, Belton DM, Graves Jr JL, and Maldonado-Devincci AM (2021). High-fat diet-induced weight gain, behavioral deficits, and dopamine changes in young C57BL/6J mice. Frontiers in Nutrition, 7: 591161. DOI: https://www.doi.org/10.33 89/fiut.2020.591161

Hargrave SL (2014). High-energy diet consumption predisposes rats to cognitive impairments, neuroinflammation, and neurovascular damage. Doctoral Dissertation, Purdue University, Indiana, United States. Available at:

https://www.proquest.com/openview/17a5178ba44b4ef71b48fdab287dc874/1?pq-origsite=gscholar&cbl=18750 Holl K, He H, Wedemeyer M, Clopton L, Wert S, Meckes JK, Cheng R Kastner A, Palmer AA, Redei EE et al. (2018). Heterogeneous stock rats: A model to study the genetics of despair-like behavior in adolescence. Genes, Brain and Behavior, 17(2): 139-148. https://www.doi.org/10.1111/gbb.12410

Hryhorczuk C, Florea M, Rodaros D, Poirier I, Daneault C, Des Rosiers C, Arvanitogiannis A, Alquier T, and Fulton S (2016). Dampened mesolimbic dopamine function and signaling by saturated but not monounsaturated dietary lipids. Neuropsychopharmacology, 41(3): 811-821. DOI: https://www.doi .org/10.1038/npp.2015.207

Hsu CC, Li Y, Hsu CT, Cheng JT, Lin MH, Cheng KC, and Chen SW (2021). Etanercept ameliorates cardiac fibrosis in rats with diet-induced obesity.

Pharmaceuticals, 14(4): 320. DOI: https://www.doi .org/10.3390/ph 14040320 Hsuchou H, He Y, Kastin AJ, Tu H, Markadakis EN, Rogers RC, Fossier PB, and Pan W (2009). Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain, 132(4): 889-902. DOI: https://www.doi.org/10.1093/brain/awp029 PMid:19293246

Hu C, Luo Y, Wang H, Kuang S, Liang G, Yang Y, Mai S, and Yang J (2017). Re-evaluation of the interrelationships among the behavioral tests in rats exposed to chronic unpredictable mild stress. PLoS One, 12(9): e0185129. DOI: https://www.doi.org/10.1371/journal.pone.0185129

Joshi A, Faivre F, La Fleur SE, and Barrot M (2021). Midbrain and lateral nucleus accumbens dopamine depletion affects free-choice high-fat high-sugar diet preference in male rats. Neuroscience, 467: 171-184. DOI: https://www.doi.org/10.1016/j .neuroscience.2021.05.022

Kaczmarczyk MM, Machaj AS, Chiu GS, Lawson MA, Gainey SJ, York JM, Meling DD, Martin SA, Kwakwa KA, Newman AF et al. (2013). Methylphenidate prevents high-fat diet (HFD)-induced learning/memory impairment in juvenile mice. Psychoneuroendocrinology, 38(9): 15531564. DOI: https://www.doi.org/10.1016/j.psyneuen.2013.01.004 Kanoski SE, Zhang Y, Zheng W, and Davidson TL (2010). The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. Journal of Alzheimer's Disease, 21(1): 207-219. DOI: https://www.doi.org/10.3233/JAD-2010-091414

Kara H and Kara A (2022). Melatonin in cardiovascular diseases. In: V. Gelen, E. §engül, and A. Kükürt (Editors), Melatonin - Recent updates. IntechOpen. DOI: https://www.doi.org/10.5772/intechopen.106085

Kraeuter AK, Guest PC, and Sarnyai Z (2019). The elevated plus maze test for measuring anxiety-like behavior in rodents. Methods in Molecular Biology, 1916: 69-74. DOI: https://www.doi.org/10.1007/978-1-4939-8994-2 4

Kuvat N, Tanriverdi H, and Armutcu F (2020). The relationship between obstructive sleep apnea syndrome and obesity: A new perspective on the pathogenesis in terms of organ crosstalk. The Clinical Respiratory Journal, 14(7): 595-604. DOI: https://www.doi .org/10.1111/crj .13175

Labban RSM, Alfawaz H, Almnaizel AT, Hassan WM, Bhat RS, Moubayed NM, Bjorklund G, and El-Ansary A (2020). High-fat diet-induced obesity and impairment of brain neurotransmitter pool. Translational Neuroscience, 11(1): 147-160. DOI: https://www.doi.org/10.1515/tnsci-2020-0099

Lai M, Chandrasekera PC, and Barnard ND (2014). You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human

obesity and diabetes. Nutrition & Diabetes, 4: e135. DOI: https://www.doi.org/10.1038/nutd.2014.30 Langley MR, Yoon H, Kim HN, Choi CII, Simon W, Kleppe L, Lanza IR, LeBrasseur NK, Matveyenko A, and Scarisbrick IA (2020). High fat diet consumption results in mitochondrial dysfunction, oxidative stress, and oligodendrocyte loss in the central nervous system. Biochimica et Biophysica Acta Molecular Basis of Disease, 1866(3): 165630. DOI: https://www.doi.org/10.1016/j.bbadis.2019.165630

Lee Y, Kroemer NB, Oehme L, Beuthien-Baumann B, Goschke T, and Smolka MN (2018). Lower dopamine tone in the striatum is associated with higher body mass index. European Neuropsychopharmacology, 28(6): 719-731. DOI: https://www.doi.org/10.1016/j.euroneuro.2018.03.009

Lerner AB, Case JD, Takahashi Y, Lee TH, and Mori W (1958). Isolation of melatonin, the pineal gland factor that lightens melanocyteS1. Journal of the American Chemical Society, 80(10): 2587-2587. DOI: https://www.doi.org/10.1021/ja01543a060

Li JH, Yu JP, Yu HG, Xu XM, Yu LL, Liu J, and Luo HS (2005). Melatonin reduces inflammatory injury through inhibiting NF-kB activation in rats with colitis. Mediators of Inflammation, 2005(4): 185-193. DOI: https://www.doi.org/10.1155/MI.2005.185

Lin CH, Huang JY, Ching CH, and Chuang JI (2008). Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. Journal of Pineal Research, 44(2): 205-213. DOI: https://www.doi.org/10.1111/j.1600-079X.2007.00510.x

Liu Z, Gan L, Xu Y, Luo D, Ren Q, Wu S, and Sun C (2017). Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-kB/GSDMD signal in mice adipose tissue. Journal of Pineal Research, 63(1): e12414. DOI: https://www.doi.org/10.1111/jpi.12414 PMid:28398673

Llorente-Folch I, Sahún I, Contreras L, Casarejos MJ, Grau JM, Saheki T, Mena MA, Satrústegui J, Dierssen M, and Pardo B (2013). AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway. Journal of Neurochemistry, 124(3): 347-362. DOI: https://www.doi.org/10.1111/jnc.12096 PMid:23216354

López-Taboada I, González-Pardo H, and Conejo NM (2020). Western diet: Implications for brain function and behavior. Frontiers in Psychology, 11:

564413. DOI: https://www.doi.org/10.3389/fpsyg.2020.564413 PMid:33329193 Maher AM, Saleh SR, Elguindy NM, Hashem HM, and Yacout GA (2020). Exogenous melatonin restrains neuroinflammation in high fat diet induced diabetic rats through attenuating indoleamine 2, 3 dioxygenase 1 expression. Life Sciences, 247: 117427. DOI: https://www.doi .org/10.1016/j.lfs.2020.117427

Mangano EN, Litteljohn D, So R, Nelson E, Peters S, Bethune C, Bobyn J, and Hayley S (2012). Interferon-y plays a role in paraquat-induced neurodegeneration involving oxidative and pro-inflammatory pathways. Neurobiology of Aging, 33(7): 1411-1426. DOI: https://www.doi.org/10.1016/j.neurobiolaging.2011.02.016 Mantovani M, Kaster MP, Pertile R, Calixto JB, Rodrigues ALS, and Santos AR (2006). Mechanisms involved in the antinociception caused by melatonin in mice. Journal of Pineal Research, 41(4): 382-389. DOI: https://www.doi.org/10.1111/j.1600-079x.2006.00380.x

282

Masek J and Fabry P (1959). High-fat diet and the development of obesity in albino rats. Experientia, 15(11): 444-445. DOI: https://www.doi.org/10.1007/BF02157708

Mashmoul M, Azlan A, Mohtarrudin N, Yusof BNM, and Khaza'ai H (2017). Saffron extract and crocin reduced biomarkers associated with obesity in rats fed a high-fat diet. Malaysian Journal of Nutrition, 23(1): 117-127. Available at: https://nutriweb.org.my/mjn/publication/23-1/k.pdf

Mayo JC, Sainz RM, Tan DX, Hardeland R Leon J, Rodriguez C, and Reiter RJ (2005). Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. Journal of Neuroimmunology, 165(1-2): 139-149. DOI: https://www.doi.org/10.1016/j.jneuroim.2005.05.002

McEwen BS (2006). Sleep deprivation as a neurobiologie and physiologic stressor: Allostasis and allostatic load. Metabolism, 55(10 Suppl 2): S20-S23. DOI: https://www.doi.org/10.1016/).metabol.2006.07.008

Montgomery SL and Bowers WJ (2012). Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. Journal of Neuroimmune Pharmacology, 7(1): 42-59. DOI: https://www.doi.org/10.1007/s11481-011-9287-2

Mota B, Ramos M, Marques SI, Silva A, Pereira PA, Madeira MD, Mateus N, and Cardoso A (2023). Effects of high-fat and high-fat high-sugar diets in the anxiety, learning and memory, and in the hippocampus neurogenesis and neuroinflammation of aged rats. Nutrients, 15(6): 1370. DOI: https://www.doi.org/10.3390/nu15061370

Mozaffarian D, Hao T, Rimm EB, Willett WC, and Hu FB (2011). Changes in diet and lifestyle and long-term weight gain in women and men. New England Journal of Medicine, 364(25): 2392-2404. DOI: https://www.doi.org/10.1056/NEJMoa1014296

Narayanaswami V, Thompson AC, Cassis LA, Bardo MT, and Dwoskin LP (2013). Diet-induced obesity: Dopamine transporter function, impulsivity and motivation. International Journal of Obesity, 37(8): 1095-1103. DOI: https://www.doi.org/10.1038/ijo.2012.178

Obayemi MJ, Akintayo CO, Oniyide AA, Aturamu A, Badejogbin OC, Atuma CL, Saidi AO, Mahmud H, and Olaniyi KS (2021). Protective role of melatonin against adipose-hepatic metabolic comorbidities in experimentally induced obese rat model. PloS One, 16(12): e0260546. DOI: https://www.doi.org/10.1371/journal.pone.0260546

Olmos G and Lladó J (2014). Tumor necrosis factor alpha: A link between neuroinflammation and excitotoxicity. Mediators of Inflammation, 2014: 861231. DOI: https://www.doi.org/10.1155/2014/861231

Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, Hardeland R, and Cardinali DP (2013). Melatonin antioxidative defense: Therapeutical implications for aging and neurodegenerative processes. Neurotoxicity Research, 23(3): 267-300. DOI: https://www.doi.org/10.1007/s12640-012-9337-4

Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, and Cardinali DP (2008). Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways. Progress in Neurobiology, 85(3): 335-353. DOI: https://www.doi .org/10.1016/j .pneurobio.2008.04.001

Panmak P, Nopparat C, Permpoonpattana K, Namyen J, and Govitrapong P (2021). Melatonin protects against methamphetamine-induced Alzheimer's disease-like pathological changes in rat hippocampus. Neurochemistry International, 148: 105121. DOI: https://www. doi.org/10.1016/j.neuint.2021.105121

Parkington HC, Abdulwahid A, and Coleman HA (2020). Maternal obesity diminishes inhibitory interneuron function in rat hippocampus. Reproductive Sciences, 27(SUPPL 1): 97A-97A.

Parkington HC, Abdulwahid AA, Mansouri FA, Finkelstein D, and Coleman HA (2019). Obesity during pregnancy in rats adversely influences brain function in the offspring as adults. pp. 1-290. DOI: https://www.doi.org/10.1016/j.orcp.2018.11.158

Pitts MW (2018). Barnes maze procedure for spatial learning and memory in mice. Bio-Protocol, 8(5): e2744. DOI: https://www.doi .org/10.21769/bioprotoc.2744

Rancan L, Paredes SD, García C, González P, Rodríguez-Bobada C, Calvo-Soto M, Hyacinthe B, Vara E, and Tresguerres JAF (2018). Comparison of the effect of melatonin treatment before and after brain ischemic injury in the inflammatory and apoptotic response in aged rats. International Journal of Molecular Sciences, 19(7): 2097. DOI: https://www.doi .org/ 10.3390/ijms19072097

Reiter RJ, Tamura H, Tan DX, and Xu XY (2014). Melatonin and the circadian system: Contributions to successful female reproduction. Fertility and Sterility, 102(2): 321-328. DOI: https://www.doi.org/10.1016/j.fertnstert.2014.06.014

Rogero MM and Calder PC (2018). Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients, 10(4): 432. DOI: https://www.doi.org/10.3390/nu10040432

Rozha SO, Hawraz FM, Harseen MR, Hassan AH, Rebin KM, Dyary HO, Lava MS, and Soz MM (2022). Green walnut husk ameliorating the adverse effects induced by high fat diet in rats. The Iraqi Journal of Veterinary Medicine, 45(2): 65-73. DOI: https://www.doi.org/10.30539/ijvm.v45i2.1286

Rudnitskaya EA, Muraleva NA, Maksimova KY, Kiseleva E, Kolosova NG, and Stefanova NA (2015). Melatonin attenuates memory impairment, amyloid-ß accumulation, and neurodegeneration in a rat model of sporadic Alzheimer's disease. Journal of Alzheimer's Disease, 47(1): 103-116. DOI: https://www.doi.org/10.3233/JAD-150161

Sabeeh RI and Khudair KK (2017). Effect of selenium and melatonin on some parameters related to metabolic syndrome induced by acryl amide in male rats (Part I). The Iraqi Journal of Veterinary Medicine, 40(2): 140-146. https://www.doi.org/10.30539/iraqijvm.v40i2.126

Sarena P, Sharma A, Urmera MT, Tambuwala MM, Aljabali AA, Chellappan DK, Dua K, Taliyan R and Goyal R (2022). Chronic light-distorted glutamate-cortisol signaling, behavioral and histological markers, and induced oxidative stress and dementia: An amelioration by melatonin. ACS Chemical Neuroscience, 13(11): 1604-1614. DOI: https://www. doi.org/10.1021 /acschemneuro .1c00531

Sepehri H, Hojat A, and Safari R (2019). Effect of bitter melon on spatial memory of rats receiving a high-fat diet. Journal of Experimental Pharmacology, 11: 115-119. DOI: https://www.doi.org/10.2147/JEP.S231260. PMid:31849540

Serafine KM, Labay C, and France CP (2016). Dietary supplementation with fish oil prevents high fat diet-induced enhancement of sensitivity to the locomotor stimulating effects of cocaine in adolescent female rats. Drug and Alcohol Dependence, 165: 45-52. DOI: https://www.doi.org/10.1016/j.drugalcdep.2016.05.013 PMid:27242289

Sharma S and Fulton S (2013). Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry. International Journal of Obesity, 37(3): 382-389. DOI: https://www.doi.org/10.1038/ijo.2012.48

Shen YX, Xu SY, Wei W, Sun XX, Liu LH, Yang J, and Dong C (2002). The protective effects of melatonin from oxidative damage induced by amyloid beta-peptide 25-35 in middle-aged rats. Journal of Pineal Research, 32(2): 85-89. DOI: https://www.doi.org/10.1034/j.1600-079x.2002.1819.x

Somade OT, Ajayi BO, Adeyi OE, Aina BO, David BO, and Sodiya ID (2019). Activation of NF-kB mediates up-regulation of cerebellar and hypothalamic pro-inflammatory chemokines (RANTES and MCP-1) and cytokines (TNF-a, IL-1 ß, IL-6) in acute edible camphor administration. Scientific African, 5: e00114. DOI: https://www.doi.org/10.1016/j.sciaf.2019.e00114

Spagnuolo MS, Mollica MP, Maresca B, Cavaliere G, Cefaliello C, Trinchese G, Scudiero S, Crispino M, and Cigliano L (2015). High fat diet and inflammation-modulation of haptoglobin level in rat brain. Frontiers in Cellular Neuroscience, 9: 479. DOI: https://www.doi .org/10.3389/ficel.2015.00479

283

Stefanova NA, Maksimova KY, Kiseleva E, Rudnitskaya EA, Muraleva NA, and Kolosova NG (2015). Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer's disease-like pathology. Journal of Pineal Research, 59(2): 163-177. DOI: https://www.doi.org/10.1111/jpi.12248

Svingos AL, Chavkin C, Colago EE, and Pickel VM (2001). Major coexpression of K-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse, 42(3): 185-192. DOI: https://www.doi.org/10.1002/syn.10005

Taher IA and Arrak JK (2016). The effect of melatonin on adrenal gland and pancreas function in alloxan - induced diabetes in adult female rabbits. The Iraqi Journal of Veterinary Medicine, 40(1): 38-46. DOI: https://www.doi.org/10.30539/iraqijvm.v40i1.136

Tan BL and Norhaizan ME (2019). Effect of high-fat diets on oxidative stress, cellular inflammatory response and cognitive function. Nutrients, 11(11): 2579. DOI: https://www.doi.org/10.3390/nu11112579

Teixeira A, Morfim MP, de Cordova CA, Charao CC, de Lima VR and Creczynski-Pasa TB (2003). Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite. Journal of Pineal Research, 35(4): 262-268. DOI: https://www.doi.org/10.1034/j.1600-079X.2003.00085.x

Tracey KJ (2007). Physiology and immunology of the cholinergic anti-inflammatory pathway. The Journal of Clinical Investigation, 117(2): 289-296. DOI: https://www.doi.org/10.1172/JCI30555 PMid:17273548

Turovsky EA, Braga A, Yu Y, Esteras N, Korsak A, Theparambil SM, Hadjihambi A, Hosford PS, Teschemacher AG, Teschemacher N et al. (2020). Mechanosensory signaling in astrocytes. Journal of Neuroscience, 40: 9364-9371. DOI: https://www.doi.org/10.1523/JNEUROSCI.1249-20.2020

Tuzcu M and Baydas G (2006). Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. European Journal of Pharmacology, 537(1-3): 106-110. DOI: https://www.doi.org/10.1016/j.ejphar.2006.03.024

Uz T, Arslan AD, Kurtuncu M, Imbesi M, Akhisaroglu M, Dwivedi Y, Pandey GN, and Manev H (2005). The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system. Molecular Brain Research, 136(1-2): 45-53. DOI: https://www.doi.org/10.1016/j.molbrainres.2005.01.002

Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C, García-Corzo L, López LC, Reiter RJ, and Acuña-Castroviejo D (2012). Extrapineal melatonin: Analysis of its subcellular distribution and daily fluctuations. Journal of Pineal Research, 52(2): 217-227. DOI: https://www.doi.org/10.1111/j .1600-079X.2011.00931 .x

Vucetic Z and Reyes TM (2010). Central dopaminergic circuitry controlling food intake and reward: Implications for the regulation of obesity. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2(5): 577-593. DOI: https://www.doi.org/10.1002/wsbm.77

Vykhovanets EV, Shankar E, Vykhovanets OV, Shukla S, and Gupta S (2011). High-fat diet increases NF-kB signaling in the prostate of reporter mice. The Prostate, 71(2): 147-156. DOI: https://www.doi.org/10.1002/pros.21230.

Wallace CW, Loudermilt MC, and Fordahl SC (2022). Effect of fasting on dopamine neurotransmission in subregions of the nucleus accumbens in male and female mice. Nutritional Neuroscience, 25(7): 1338-1349. DOI: https://www.doi.org/10.1080/1028415X.2020.1853419

Welser-Alves JV and Milner R (2013). Microglia are the major source of TNF-a and TGF-P1 in postnatal glial cultures; regulation by cytokines, lipopolysaccharide, and vitronectin. Neurochemistry International, 63(1): 47-53. DOI: https://www.doi.org/10.1016/j.neuint.2013.04.007

Wolburg H and Lippoldt A (2002). Tight junctions of the blood-brain barrier: Development, composition, and regulation. Vascular Pharmacology, 38(6): 323-337. DOI: https://www.doi.org/10.1016/s1537-1891(02)00200-8

Xu J, Gao H, Zhang L, Rong S, Yang W, Ma C, Chen M, Huang Q, Deng Q, and Huang F (2019). Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high-fat diet. Journal of Pineal Research, 67(2): e12584. DOI: https://www.doi.org/10.1111/jpi.12584

Xu LX, Lv Y, Li YH, Ding X, Wang Y, Han X, Liu MH, Sun B, and Feng X (2017). Melatonin alleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: The involvement of edema related proteins. BMC Pediatrics, 17: 90. DOI: https://www.doi .org/10.1186/s12887-017-0824-x

Yapislar H, Haciosmanoglu E, Sarioglu T, Degirmencioglu S, Sogut I, Poteser M, and Ekmekcioglu C (2022). Anti-Inflammatory effects of melatonin in rats with induced type 2 diabetes mellitus. Life, 12(4): 574. DOI: https://www.doi.org/10.3390/life12040574

Yeung AY and Tadi P (2020). Physiology, obesity neurohormonal appetite and satiety control. StatPearls. StatPearls Publishing., Treasure Island (FL).

Yin J, Jin X, Shan Z, Li S, Huang H, Li P, Peng X, Peng Z, Yu K, Bao W et al. (2017). Relationship of sleep duration with all-cause mortality and cardiovascular events: A systematic review and dose-response meta-analysis of prospective cohort studies. Journal of the American Heart Association, 6(9): e005947. DOI: https://www.doi.org/10.1161/jaha.117.005947

Zhang H, Wei M, Sun N, Wang H, and Fan H (2022). Melatonin attenuates chronic stress-induced hippocampal inflammatory response and apoptosis by inhibiting ADAM17/TNF-a axis. Food and Chemical Toxicology, 169: 113441. DOI: https://www.doi.org/10.1016/j.fct.2022.113441

Zhang S, Wang P, Ren L, Hu C, and Bi J (2016). Protective effect of melatonin on soluble Ap1-42-induced memory impairment, astrogliosis, and synaptic dysfunction via the Musashi1/Notch1/Hes1 signaling pathway in the rat hippocampus. Alzheimer's Research & Therapy, 8(1): 1-8. DOI: https://www.doi.org/10.1186/s13195-016-0206-x

Zisapel N (2001). Melatonin-dopamine interactions: From basic neurochemistry to a clinical setting. Cellular and Molecular Neurobiology, 21(6): 605616. DOI: https://www.doi.org/10.1023/A:1015187601628

Publisher's note: Scienceline Publication Ltd. remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

|(cc) ® | Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2023

284