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6J.J. Bakhronov, S.Z. Ubaydullayev, Sh.B. Jamoliddinov, M.N. Nigmatullaev, M.M. Kuddusov, R.N. Muhiddinzoda, D.G. Nizamova, Sh.Sh. Turaev, M.A. Kholikulova
PATHOGENESIS OF NARCOLEPSY
This article provides a review of the literature and scientific experiment on the pathogenesis of narcolepsy. The structures responsible for maintaining the body's wakefulness, the consequences of disruption of the functioning of these structures, the history of the development of interest in this topic among neurologists are included. Pathogenesis of narcolepsy.
Keywords: Narcolepsy, pathogenesis of narcolepsy, orexin/hypocretin, human leukocyte antigen, cataplexy, REM sleep, experiment on transgenic mice.
In the early 20th century, a pandemic influenza virus caused encephalitis and many people suffered from sleep disorders. During this time period, the Viennese physician von Economo, examining the post-mortem brains of these patients, predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting area in the preoptic region. Seventy years later, two independent research groups identified a neuropeptide: orexin/hypocretin (both names are used in different sources, meaning the same neuropeptide). The posterior lateral hypothalamus has been found to contain orexin/hypocretin neurons, which are critical for maintaining normal wakefulness. Shortly after their discovery, orexin neurons were found to be associated with the phenomenon of "narcolepsy," which is a sleep disorder characterized by excessive daytime sleepiness and sudden, emotionally triggered muscle weakness. Several animal and human studies have been carried out and the results have been presented: canine narcolepsy has been identified as a mutation in the orexin-2 (hypocretin-2) receptor; Murine narcolepsy has been identified as a lack of orexin action on neurons containing the orexin-2 receptor. In the case of humans, the concentration of orexin in the cerebrospinal fluid of patients with narcolepsy was lower than that of healthy individuals.
Statistics: The prevalence of narcolepsy in the population is from 0.03 to 0.16%, usually the first symptoms of the disease appear in adolescence or early adulthood. This sleep disorder is equally common among men and women.
There are no epidemiological data on narcolepsy in the CIS countries. In the US, the prevalence of narcolepsy is 0.5-1 per 1000 inhabitants (only four times less than patients with Parkinson's disease). The highest prevalence of such patients in Japan (1 per 600 people), and the lowest - in Israel (1 per 500,000 inhabitants).
Pathogenesis: Characteristically, the onset of symptoms of narcolepsy is often preceded by streptococcal infection, tick-borne encephalitis, and traumatic brain injury.
However, the causes of this disease have not been fully studied, but at the moment it has been established that the hypothalamic peptide "orexin" plays a leading role in the development of narcolepsy, the decrease or absence of which in the posterior parts of the hypothalamus leads to disturbances in the physiological cycle "sleep-wakefulness". It has been established that the system of orexinergic neurons is one of the main regulators of wakefulness and, in case of pathology, is present in the slow phase of sleep. Its neurons project onto noradrenergic cells in the locus coeruleus, causing their activation. The lack of this leads to the fact that locus coeruleus neurons acquire the ability to suddenly "silence" not only during REM sleep, but also during wakefulness, contributing to the onset of narcolepsy attacks. The insufficiency of the orexin system leads to the formation of a narcoleptic phenotype with its inherent disturbances in the interaction between the mechanisms of wakefulness, non-REM and REM sleep.
The above is confirmed by an experiment on transgenic mice with overexpression of human orexin/hypocretin under the control of its endogenous promoter, in which an increased expression of human pre-proorexin (hPPO) and orexin-A was detected in the hypothalamus of mice. Transgene expression reduced endogenous orexin-2 receptors but not orexin-1 receptors in the hypothalamus without affecting orexin receptor levels in the basal forebrain, cortex, or hippocampus. The transgenic mice showed changes in the duration of wakefulness
© J.J. Bakhronov, S.Z. Ubaydullayev, Sh.B. Jamoliddinov, M.N. Nigmatullaev, M.M. Kuddusov, R.N. Muhiddinzoda, D.G. Nizamova, Sh.Sh. Turaev, M.A. Kholikulova, 2023.
and non-REM sleep compared to mice in the wild, especially during periods of light-to-dark transition, in addition to a slight reduction in REM sleep at baseline and during restorative NREM.
It has been shown that 90% of people with narcolepsy carry a particular variant of the human leukocyte antigen (HLA) group of genes, while in the general population this variant occurs only in 25% of cases. Based on these data, an autoimmune theory of damage to hypocretinergic neurons as a result of a genetic mutation was formulated. This lesion becomes possible due to the presence of the HLA-DQB1 gene of the HLA histocompatibility system, or rather, one of its alleles - HLA-DQB1*06:02. It is noteworthy that mutations of a different nature in the same allele were associated with the development of other diseases, such as diabetes mellitus, multiple sclerosis, or celiac disease. It is assumed that the autoimmune reaction in narcolepsy develops due to the fact that the abnormal HLA protein resulting from the mutation (HLA-DQB1 * 06:02), expressed on oligodendrocytes, through microglia, presents the antigen of orexinergic neurons to CD4 + cells, which is normal for the immune system. system should not be alien. This complex triggers a cascade of changes that ultimately leads to the activation of CD8+ cells and to the provocation of a cytotoxic reaction. Until recently, such cells could not be detected, but in recent studies they have not only been identified, but also a specific substance has been identified that is the target for the attack of CD8+ cells: the autoimmune reaction was directed not only against hypocretin-1 and hypocretin-2, but also another intracellular component of the hypocretinergic neuron - TRIB2 (belongs to the class of atypical kinases); and a detailed screening of CD4+ cells made it possible to determine that the reaction of aggression is not in relation to a specific sequence of peptides in hypocretin, but to its various antigenic determinants. However, in the preparations of dead sick animals from narcolepsy in the region of the lateral hypothalamus, where orexinergic neurons are located, an increased infiltration of only CD8+ cells, but not CD4+, was found. In addition, an increased concentration of IFN-y (interferon-gamma) was found in the cerebrospinal fluid in narcolepsy. The activity of CD4+ cells, according to the latest data, is directly proportional to the level of IFN-y in the cerebrospinal fluid. It is also known about some association of narcolepsy symptoms with another HLA gene DRB1*15:01, in which case the disease develops according to the same mechanisms as with DQB1*06:02, but more often the DRB1*15:01 mutation is a marker of predisposition to development multiple sclerosis, although there are cases of narcolepsy in combination with this demyelinating disease. However, it has been found that in some cases, the presence of the HLA-DQB1*06:02 mutation alone is not enough, and the DRB1*15:01 mutation is also required. The intensity of the clinical manifestations of narcolepsy seems to depend on the number of alleles of the HLA genes - DQB1*06:02 and DRB1*15:01, which are expressed in cells. This is shown not only for the severity of the manifestation of the disease, but also for the age of onset of the disease.
However, not all cases of clinically apparent narcolepsy show a mutation in the HLA system gene. What in such cases can cause the development of this disease? Another mutation is thought to be responsible, this time located on chromosome 19 in the P2RY11 gene. This gene encodes the sequence of amino acids necessary for the assembly of the P2Y11 receptor. The P2Y11 receptor is predominantly expressed on CD8+ cells and NK cells. The function of this receptor is not definitively known, until it is found to be a G-coupled receptor (Gs- and Gq-type receptors) that is activated by nucleoside phosphate esters such as adenosine triphosphate, adenosine diphos-phate, uridine triphosphate, uridine diphosphate. As a consequence of this activation, there is an increase in intra-cellular Ca2+ concentration through the phosphatidylinositol pathway and cAMP levels through the activation of adenylate cyclase.
Within a year after the onset of narcolepsy, generalized attacks of cataplexy join. Cataplexy is considered as an episode of the onset of the sleep phase of rapid eye movements during wakefulness. Normally, orexin secretion, which is maximal during periods of wakefulness, maintains muscle tone through the activation of locus co-eruleus neurons and raphe nuclei, which in turn increase the activity of spinal cord interneurons. The main neurotransmitters of these functional systems are norepinephrine and serotonin. With a decrease in the concentration of hypocretin, the balance of neurotransmitter systems is disturbed, under certain conditions even in the waking state, causing activation of inhibitory descending influences on the segmental apparatus of the spinal cord: on interneurons, and through them on the lower motor neurons, which leads to a loss of muscle tone.
An important feature of narcolepsy is also a change in eating behavior with subsequent weight gain. Obesity in patients with narcolepsy was described several decades ago, but this phenotype has been neglected as it may be secondary to behavioral changes (inactivity). However, a study of mice with hypocretin neuron ablation showed that these animals exhibit hypophagia and late-onset obesity, possibly associated with reduced energy expenditure or a low metabolic rate. A decrease in calorie intake has also been reported in some people.
Conclusion: The leading role in the development of narcolepsy is played by the hypothalamic peptide "orexin", a decrease in the amount of which leads to the development of symptoms of narcolepsy. In the development of narcolepsy, importance is also attached to the presence of the HLA-DQB 1 gene of the HLA histocompatibility system, or rather, one of its alleles, HLA-DQB1 * 06:02, in the human body.
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BAKHRONOV JAKHONGIR JASUROVICH - student of the 521st group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
UBAYDULLAEVSARDOR ZAFAROVICH - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
JAMOLIDDINOVSHERALIBAXTIYOR UGLI - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
NIGMATULLAEV MUHAMMADJON NURALIYEVICH - student of the 522st group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
KUDDUSOVMUSLIMBEK MUHSIN UGLI - student of the 522th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
MUHIDDINZODA RUKHSHONABONUNUMONKIZI - student of the 221st group of the medical faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
NIZAMOVA DILSHODA GAYRATJONOVNA - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
TURAEVSHOKHRUKHSHERALI UGLI - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
KHOLIKULOVA MAKHBUBA ANVAR KIZI - student of the 507th group of the pediatric faculty of the Samarkand State Medical University, Samarkand, Uzbekistan.
