Evaluation of the effect of the neurotoxin MPTP and the antiparkinsonian drug hemantane on the DNA integrity in the brain structures of C57BL/6 mice
https://doi.org/10.37489/2587-7836-2021-4-47-52
Abstract
Hemantane (N-adamant-2-yl-hexamethylenimine hydrochloride) is an antiparkinsonian drug with a multicomponent mechanism of action, including a modulating effect on the activity of dopamine and serotonergic mediator systems, a selective inhibitory effect on MAO-B, properties of a low-affinity non-competitive channel blocker of glutamate NMDA receptors, has moderate antiradical and anti-inflammatory activity. The aim of this study was to assess the effect of the neurotoxin MPTP, which is used for modeling of parkinsonian syndrome, and the hemantane on the DNA integrity in the striatum and frontal cortex of the brain of C57BL/6 mice by the DNA comet assay – gel electrophoresis of DNA single cells. Results. In the first experiment, hemantane was administered once a day for 5 days before the MPTP (20 mg/kg, i.p.), then together with MPTP once a day for 5 days. In the second experiment hemantane 10 mg/kg was injected preliminarily for 4 days and 40 minutes before MPTP 30 mg/kg. The obtained results confirm the absence of an effect on DNA of hemantane at a therapeutic dose of 10 mg / kg. In the experimental schemes used, we did not reveal the expected increase in the level of DNA damage under the influence of MPTP, and, accordingly, we were not able to assess the protective effect of hemantane.
About the Authors
E. A. Anisina
FSBI “Zakusov Institute of Pharmacology”
Russian Federation
Russian Federation
Anisina Elena A. - junior researcher, laboratory of pharmacology of mutagenesis
Moscow
A. K. Zhanataev
FSBI “Zakusov Institute of Pharmacology”
Russian Federation
Russian Federation
Zhanataev Aliy K.- Leading researcher, laboratory of pharmacology of mutagenesis
SPIN code: 7070-0510
Moscow
A. V. Nepoklonov
FSBI “Zakusov Institute of Pharmacology”
Russian Federation
Russian Federation
Nepoklonov Alexey V. - Junior researcher, laboratory of psychopharmacology
Moscow
S. O. Kotelnikova
FSBI “Zakusov Institute of Pharmacology”
Russian Federation
Russian Federation
Kotelnikova Svetlana O. - Senior researcher, laboratory of psychopharmacology
Moscow
E. A. Valdman
FSBI “Zakusov Institute of Pharmacology”
Russian Federation
Russian Federation
Valdman Elena A. - Leading researcher, laboratory of psychopharmacology
SPIN code: 6806-3799
Moscow
References
1. Tissingh P, Bergmans J, Booij A et al. Drug-naive patients with Parkinson’s disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta- CIT SPECT. J Neurol. 1998;245(1):14–20. DOI: 10.1007/s004150050168.
2. Abaimov DA, Zimin IA, Kovalev GI. Subchronic effects of hemantane on the main subtypes of dopamine receptors in rat striatum ex vivo. Experimental and clinical pharmacology. 2008;71(1):18–21. (In Russ).
3. Abaimov D, Zimin I, Kudrin V, Kovalev G. Effects of antiparkinsonian drug hemantane on the level and metabolism of biogenic monoamines in brain structures of C57BL/6 mice. Experimental and clinical pharmacology. 2009;72(1):64–67. (In Russ).
4. Andiarzhanova EA, Valdman EA, Kudrin VS et al. Effect of a novel potential antiparkinsonian drug hemantane on the content of monoamines and its metabolites in the striatum of rats (microdialysis assay). Experimental and Clinical Pharmacology. 2001;64(6): 13–17. (In Russ).
5. Valdman EA, Voronina TA, Aksenova LN et al. Effect of a new antiparkinsonian drug hemantane on monoamine oxidase activity. Experimental and Clinical Pharmacology. 2003;5:3–5. (In Russ).
6. Valdman EA, Kapitsa IG, Nerobkova LN et al. The effect of long-term administration of isatin and himantan to mice on sensitivity of brain monoamine oxidase B to inhibition by deprenyl in vivo and in vitro. Biomeditsinskaya Khimia 2004;50(5): 509–513 (In Russ).
7. Elshanskaia MV, Sobolevskiĭ AI, Val'dman EA, Khodorov BI. Effect of the potential antiparkinsonian agent adamantane derivative on ion channels of NMDA glutamate receptors. Experimental and Clinical Pharmacology. 2001;64(1):18–21. (In Russ).].
8. Estimation of the prolonged immunotropic effect of the new potential antiparkinsonian drug himantane. Experimental and Clinical Pharmacology. 2003;66(3): 44–46. (In Russ). DOI: 10.30906/0869-2092-2003-66-3-44-46.
9. Ivanova ЕА, Kapitsa IG, Zolotov NN, Valdman EA, Nepoklonov АV, Kolyasnikova KN, Voronina ТА. Effects of Hemantane upon the level of lipid peroxidation in brain in experimental parkinsonian syndrome. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2016;(3):9–12. (In Russ).
10. Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem. 1992;59(5):1609–1623. DOI: 10.1111/j.1471–4159.1992.tb10990.x.
11. Hald A, Lotharius J. Oxidative stress and inflammation in Parkinson’s disease: is there a causal link? Experimental Neurology. 2005;193(2):279–290. DOI: 10.1016/j.expneurol.2005.01.013.
12. Durnev AD, Merkulov VA, Zhanataev AK et al. Guidelines for the assessment of DNA damage by alkaline gel electrophoresis of single cells in pharmacological studies. Guidelines for preclinical studies of drugs. Part one. Ed. A.N. Mironov. Moscow: 2012. (In Russ).
13. Nepoklonov AV. Study of the effects of hemantane on the early stages of Parkinson’s disease and levodopa-induced dyskinesia (experimental study). [dissertation]. Moscow; 2013. (In Russ).
14. Konca K, Lankoff A, Banasik A. A cross-platform public domain PC image-analysis program for the comet assay. Mutat Res. 2003;534(1-2): 15–20. DOI: 10.1016/s1383-5718(02)00251-6.
15. Moller P., Loft S. Statistical analysis of comet assay results. Front Genet. 2014;5:292. DOI: 10.3389/fgene.2014.00292.
16. Schmidt N, Ferger B. Neurochemical findings in the MPTP model of Parkinson’s disease. J Neural Transm (Vienna). 2001;108(11):1263–1282. DOI: 10.1007/s007020100004.
17. Hoang T, Choi DK, Nagai M. et al. Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease. Free Radic Biol Med. 2009;47(7):1049–1056. DOI: 10.1016/j.freeradbiomed.2009.07.013.
18. Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S. Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration. 1995;4(3):257–269. DOI: 10.1016/1055-8330(95)90015-2.
19. Zhanataev AK, Anisina EA, Chaika ZV, Miroshkina IA, Durnev AD. The phenomenon of atypical DNA comets. Citologia. 2017;59(3):163–168. (In Russ).
20. Coetsee N, Pretorius PJ, Terre Blanche G, Bergh JJ. Investigating the potential neuroprotective effects of statins on DNA damage in mouse striatum. Food Chem Toxicol. 2008;46(9):3186–3192. DOI: 10.1016/j.fct.2008.07.006.
21. Meredith GE, Rademacher DJ. MPTP mouse models of Parkinson's disease: an update. J Parkinsons Dis. 2011;1(1):19–33. DOI: 10.3233/JPD-2011-11023.
22. Pickrell AM, Pinto M, Hida A, Moraes CT. Striatal dysfunctions associated with mitochondrial DNA damage in dopaminergic neurons in a mouse model of Parkinson's disease. J Neurosci. 2011;31(48):17649–17658. DOI: 10.1523/JNEUROSCI.4871-11.2011.
Review
For citations:
Anisina E.A., Zhanataev A.K., Nepoklonov A.V., Kotelnikova S.O., Valdman E.A. Evaluation of the effect of the neurotoxin MPTP and the antiparkinsonian drug hemantane on the DNA integrity in the brain structures of C57BL/6 mice. Pharmacokinetics and Pharmacodynamics. 2021;(4):47-52. (In Russ.) https://doi.org/10.37489/2587-7836-2021-4-47-52
Views:
403
Email this article 