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Section 2. Medical science
Azamatov Azizbek Azamat o'gli Junior Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent E-mail: [email protected] Rejepov Jumadilla
Leading Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent Tursunkhodjaeva Firuza Muratovna Senior Scientific Researcher of Department of Pharmacology and Toxicology of Institute of Chemistry of Plant Substances, Academy of Sciences of Republic of Uzbekistan, Tashkent
ANTITOXIC EFFECTS OF TWO NEW N-BENZOYL DERIVATIVES OF CYTISINE IN ACUTE AND CHRONIC ALCOHOL INTOXICATION
Abstract: Antitoxic effects of new N-benzoyl derivatives of cytisine in acute and chronic ethanol intoxication have been investigated. It has been established that the test substances have a pronounced antitoxic effect in acute alcohol intoxication and improve animal orientation and exploratory behaviour in chronic alcohol intoxication.
Keywords: Cytisine derivatives, toxicity, antitoxic activity, anesthesia, acute intoxication, chronic intoxication, orientation and exploratory behaviour.
Nicotinic acetylcholine receptors (nAChR) are known purpose of this study is the evaluation of neuroprotective and
to attract the interest of numerous researchers, since the antitoxic effects of new N-benzoyl derivatives of cytisine: N-
cholinergic system occupies one of the key positions in the benzoylcytizine hydrochloride and N-hydroxyethylcytizine development of neurodegenerative brain diseases, includ- hydrochloride in acute and chronic alcohol toxicity. ing Alzheimer's disease, Parkinson senile dementia, as well Materials and methods of investigation. The effect of
as alcoholism, drug addiction, etc. They activate higher inte- studied drugs on acute alcohol intoxication was investigated
grative activity of brain, restore impaired mnestic and mental on white mice males weighing 18-20 grams. The animals were
functions, reduce neurological deficit and increase the body's injected intraperitoneally with 24% aqueous ethanol solution
resistance to various extreme factors [1-4]. Severe cholinergic at a dose of 4.8 g/kg. The time of onset and termination of
dysfunction, density and plasticity of cholinergic receptors alcohol anesthesia ("lateral position") was recorded. The stud-
decreasing were observed in various types of amnesia [5-9]. ied substances were administered at doses of 0.1-0.5-1.0-5.0 Currently, nAChR are considered as an interesting target for mg/kg subcutaneously in 30 minutes before ethanol injection.
the development of new drugs for the treatment of central Each dose was tested on 10 mice. Pentyleneterazole and caf-
nervous system dysfunctions [8-9]. feine were used as a reference drugs.
Cytisine has a high affinity for many nAChR subtypes, Chronic intoxication was caused by daily intragastric ad-
but low penetration through the blood-brain barrier due to ministration of a 15% ethanol solution at a dose of 4 g/kg using low lipophilicity [6-9]. The targeted research to create new an atraumatic metal probe for 30 days. Ethanol introduction
products based on N-benzoyl cytisine derivatives carry out was stopped from 31th day and experimental therapy with the
in the Institute of Chemistry of Plant Substances of the Acad- studied drugs was carried out for 7 days at doses of 0.1-0.5-
emy of Sciences of the Republic of Uzbekistan [10-12]. The 1.0-5.0 mg/kg subcutaneously followed by testing for orien-
ANTITOXIC EFFECTS OF TWO NEW N-BENZOYL DERIVATIVES OF CYTISINE IN ACUTE AND CHRONIC ALCOHOL INTOXICATION
tation and exploratory behaviour of mice in the "open field". The locomotor activity was evaluated by the number of crossed squares, the research activity by the number of peeking into the hole, the orientation — by the number of stands on hind legs. Each dose of the substance was tested on 10 animals. The control group of mice under the same experimental conditions was administered sterile distilled water instead the investigated substance. Piracetam was used subcutaneously as an ethalon drug at a dose of 400 mg/kg. The study of acute toxicity was performed on mice with subcutaneous method of application.
Results and discussion
It was established that intraperitoneal administration of 24% ethanol solution at a dose of 4.8 g/kg causes anesthesia (lateral position) in 100% of experimental and control ani-
The study of orientation and exploratory behaviour in "open field" in chronic alcohol intoxication for 30 days showed that prolonged use of ethanol leads to a significant suppression of locomotor activity and an exploratory behaviour compared to control animals. So, in animals receiving only ethanol, locomotor activity (the number of crossed squares was 4.6 ± 1.0, the control was 11.8 ± 1.2), orientation (the number of racks on hind legs was 1.8 ± 0.2, control — 5.6 ± 0.6) and research activity (the number of peering into the holes is 5.2 ± 0.6, the control is 13.7 ± 1.3) reduced. The use of N-benzoylcytisine
mals. In the control group, the average duration of anesthesia was 119.2 minutes. Preliminary use of N-benzoylcytisine hydrochloride and N-hydroxyethylcytisine hydrochloride had a pronounced analeptic effect. N-benzoylcytisine hydrochloride at doses of 0.1-0.5-1.0-5.0 mg/kg shortened the duration of anesthesia compared with the control group of animals by 19.5%, 40.3%, 43.4%, and 34.4%, respectively. Under the same experimental conditions, N-hydroxyethylcytisine hydrochloride reduced the lateral position of mice compared to the control group of animals by 27, 7, 30, 36.1, and 28.4%, respectively. Both cytisine N-benzoyl derivatives were not inferior to pentyleneterazole and caffeine in comparison with the ethalon drugs, and even exceeded its effect at doses of 0.5 and 1.0 mg/kg (Table 1).
and N-hydroxyetylcytisine hydrochlorides at a dose of 0.1 mg/kg increased the number of horizontal movements to 6.4 ± 0.8 and 6.1 ± 1.0, the number of vertical stands to 3.2 ± 0.6 and 2.9 ± 0.5, and the number of holes inspection up to 8.4 ± 0.5 and 7.9 ± 0.7, respectively. Increasing the dose of substances to 0.5 mg/kg and 1.0 mg/kg significantly increases the locomotor and research activity in the "open field" to almost the control values. With further increase of the dose to 5.0 mg/kg leads to decreasing of the abovementioned values (Table 2).
Table 2. - Effects of investigated substances in the "open field" in chronic alcohol intoxication (n=10)
No. Animal groups Doses, mg/kg Horizontal movies Vertical stands Holes inspection
1 2 3 4 5 6
1 Control (distilled water) 11.811.2 5.6±0.6 13.711.3
2 Ethanol 4000 4.6±0.5 1.810.4 5.210.6
Table 1. - Effects of cytisine N — benzoyl derivatives on acute alcohol intoxication (n=10)
No. Animal group Dose, mg/kg s/c Duration, Effectiveness, %
minutes %
1 Ethanol 4.8 g/kg i/p - 119.2±5.3 100% -
2 Pentylenetetrazole 10 87.6±7.4 73.4% -26.6%*
3 Caffeine 10 79.4±7.6 66.6% -33.4%*
4 N-benzoylcytisine hydrochloride 0.1 96.0±8.0 80.5% -19.5%
0.5 71.2±6.8 69.3% -40.3%*
1.0 67.5±5.9 56.6% -43.4%*
5.0 78.2±6.3 65.6% -34.4%*
5 N-hydroxyethylcytisine hydrochloride 0.1 86.2±7.8 72.3% -27.7%*
0.5 83.5±6.5 70.0% -30.0%*
1.0 76.2±6.8 63.9% -36.1%*
5.0 85.4±5.6 71.6% -28.4%*
Note: *P<0.05.
1 2 3 4 5 6
3 N-benzoylcytisine hydro- 0.1 6.4±0.8 3.2±0.6 8.4±1.1
chloride 0.5 10.9±0.8 5.0±0.8 12.9±1.3
1.0 10.0±1.2 5.3±0.4 13.6±0.9
5.0 8.4±0.9 3.8±0.3 7.4±0.6
4 N-hydroxyethylcytisine 0.1 6.1±1.0 2.9±0.5 7.9±0.7
hydrochloride 0.5 9.8±1.2 4.6±0.6 10.2±0.8
1.0 12.1±0.9 5.2±0.8 12.8±1.2
5.0 7.4±0.8 3.8±0.4 8.1±1.0
5 Piracetam 400 8.8±1.2 4.0±0.6 9.6±1.4
The average lethal dose (LD50) of N-benzoylcytisine hydrochloride and N-hydroxyethylcytisine hydrochloride at subcutaneous administration were found to be 81 (70 ± 93.1) mg/kg and 435 (381 ± 495) mg/kg, respectively.
Conclusions:
1. N-benzoyl derivatives of cytisine exhibit pronounced anti-narcotic action in acute alcohol intoxication.
2. New N-benzoyl cytisine derivatives have increase the locomotor activity, orientation and exploratory behaviour of animals in the "open field" after long-term alcohol intoxication.
References:
1. Mashkovskiy M. D. Medicinal preparations. Tashkent, Medicine, 1998. V.1, P. 108-116.
2. Wuller W. E., Meth. Fiind. Exp.clin. pharmacol. 1988, Vol. 10, No.12, P. 773-783.
3. Voronina T. A. Pharmacology and toxicology J., 2016. V. 54, No.2, P. 6-12.
4. Belenichev I. V., Kucher T. V., Kucherenko L. I., Morgunzhova S. A. Bulletin of new medical technologies. V. 21. No.3. P. 85-90, 2014.
5. Donold A. Me., Cosfozd N., Vernior J. M., Ann. Rep. Med. Chem., 30, 41, 1995.
6. Holladeg M. W., Dart M. J., Lunch J. K., J. Med. Chem., 40, 4169, 1997.
7. Jensen A. A., Frolud B., Liljefors T., Krogsgaard P.- Lorsen, J. Med. Chem, 48, 4705, 2005.
8. Chellepan S. K., Xiao Y., Tueckmantel W., Kellar K. J., Kozikowski A. P., J. Med. Chem., 49, 2673, 2006.
9. Fitch R. W., KanekoY., Klapershi P., Daly J. W., Seitz G., Gundiser D., Bioorg. Med. Chem. Let., 15, 1221, 2005.
10. Rakhimov Sh.B., Vinogradova V. I., MirzaevYu.R., Vipova V. P., Kazantsev D. S., Khimiya prirodnyh soedinenii, 2006. No.4, p. 373-378.
11. Azamatov A. A., Rejepov J., Tursunkhodjaeva F. M. et. al., European science review J., 2018.- No. 5-6.- P. 123-126.
12. Azamatov A. A., Tursunkhodjaeva F. M., RejepovJ. et. al., European science review J., 2018.- No. 7-8.- P. 80-83.
13. Azamatov A. A. European science review J., 2018.- No. 9-10.- P. 6-8.
