Afobazole prevents motor function impairment in mice with 6-OHDA induced Parkinsonism
https://doi.org/ 10.24411/2587-7836-2018-10017.
Abstract
Resume. Objective. Current insufficiency in treatment of Parkinson’s disease determines the search for new pharmacological targets to achieve neuroprotection and reduce the severity of motor impairment. It is known that ligand activation of chaperone sigma-1 (SigmaR1) and inhibition of quinone reductase 2 (NQO2) cause cytoprotection. Anxiolytic drug afobazole (5-Ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihidrochloride) interacts with SigmaR1 and regulatory site of NQO2, inhibiting it. In vivo and in vitro experiments have demonstrated neuroprotective effect of afobazole. However, the effect of afobazole on motor deficit and motion coordination in model of Parkinson’s disease was not studied. Aim. To study the influence of afobazole on latency to fall in rotarod test in mice with induced 6-hydroxydopamine (6-OHDA) Parkinsonism. Methods. Male CD-1 (ICR) mice were tested at accelerated and constant speed rotarod. Afobazole was administered during 14 days (2.5 mg/kg, ip) at course start 30 minutes after unilateral intrastriatal injection of 5 |xg 6-OHDA. Results. Chronic administration of afobazole (2.5 mg/kg) to hemiparkinsonian mice increases their latency to fall 3.9 fold contrary to placebo treated mice in constant speed rotarod. Afobazole negates 6-OHDA in accelerating rotarod increasing latency to fall 1.6 fold as compared to placebo group. Conclusion. Afobazole prevents motor function impairment in hemiparkinsonian mice with 6-OHDA lesion in rotarod test. Observed effect of afobazole can be a result of it neuroprotective properties derived from SigmaR1 and NQO2 interaction.
About the Authors
I. A. Kadnikov
FSBI «Zakusov Institute of Pharmacology»
Russian Federation
Russian Federation
M. V. Voronin
FSBI «Zakusov Institute of Pharmacology»
Russian Federation
Russian Federation
S. B. Seredenin
FSBI «Zakusov Institute of Pharmacology»
Russian Federation
Russian Federation
References
1. Ebrahimi-Fakhari D., Saidi LJ, Wahlster L. Molecular chaperones and protein folding as therapeutic targets in Parkinson's disease and other synucleinopathies. Acta Neuropathol Commun. 2013;1:79. DOI: 10.1186/2051-5960-1-79
2. Hayashi T., Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007;131(3):596-610. DOI: 10.1016/j.cell.2007.08.036
3. Harada S, Fujii C, Hayashi A, et al. An association between idiopathic Parkinson's disease and polymorphisms of phase II detoxification enzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2. Biochem Biophys Res Commun. 2001;288(4):887- 892. DOI: 10.1006/ bbrc.2001.5868
4. Nguyen L., Lucke-Wold BP, Mookerjee SA, et al. Role of sigma-1 receptors in neurodegenerative diseases. J. Pharmacol Sci. 2015;127(1):17-29. DOI: 10.1016/jjphs.2014.12.005
5. Su TP, Su TC, Nakamura Y., et al. The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems. Trends Pharmacol Sci. 2016;37(4):262-278. DOI: 10.1016/j.tips.2016.01.003
6. Ruscher K., Wieloch T. The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration. J. Pharmacol Sci. 2015;127(1):30-35. DOI: 10.1016/j.jphs.2014.11.011.
7. Vella F., Ferry G., Delagrange P., et al. NRH:quinone reductase 2: an enzyme of surprises and mysteries. Biochem Pharmacol. 2005;71(1-2):1-12. DOI: 10.1016/j.bcp.2005.09.019
8. Segura-Aguilar J., Paris I., Mucoz P., et al. Protective and toxic roles of dopamine in Parkinson's disease. J. Neurochem. 2014;129(6):898-915. DOI: 10.1111/jnc.12686
9. Reybier K., Perio P., Ferry G., et al. Insights into the redox cycle of human quinone reductase 2. Free Radic Res. 2011;45(10):1184- 1195. DOI: 10.3109/10715762.2011.605788
10. Asanuma M., Miyazaki I., Diaz-Corrales FJ, et al. Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism. Acta Med Okayama. 2004;58(5):221-233. DOI: 10.18926/AMO/32105
11. Cassagnes LE, Chhour M., Perio P., et al. Oxidative stress and neurodegeneration: The possible contribution of quinone reductase 2. Free Radic Biol Med. 2018;120:56-61. DOI: 10.1016/j.freeradbiomed.2018.03.002
12. Середенин С.Б., Воронин М.В. Нейропротекторные механизмы действия афобазола // Экспериментальная и клиническая фармакология. - 2009. - Т. 72. - №1. - С.3- 11.
13. Kadnikov IA, Voronin MV, Seredenin SB. Effect of afobazole on activity of quinone reductase 2. Pharmaceutical Chemistry Journal. 2014;47(10):514-516. DOI: 10.1007/s11094-014-0993-y
14. Voronin MV, Kadnikov IA. Contribution of Sigma-1 receptor to cytoprotective effect of afobazole. Pharmacol Res Perspect. 2016;4(6):e00273. DOI: 10.1002/prp2.273
15. Behensky AA, Yasny IE, Shuster AM, et al. Stimulation of Sigma Receptors with Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-beta25-35. J. Pharmacol Exp Ther. 2013;347(2):458-467. DOI: 10.1124/jpet.113.208348
16. Behensky AA, Yasny IE, Shuster AM, et al. Afobazole Activation of sigma-1 Receptors Modulates Neuronal Responses to Amyloid-beta25-35. J. Pharmacol Exp Ther. 2013;347(2):468-477. DOI: 10.1124/jpet.113.208330
17. Воронин М.В., Кадников И.А., Середенин С.Б. Афобазол восстанавливает содержание дофамина при моделировании болезни Паркинсона 6-гидроксидофамином Афобазол восстанавливает содержание дофамина при моделировании болезни Паркинсона 6-гидрок-сидофамином // Нейрохимия. 2019 (в печати)
18. Blum D., Torch S., Lambeng N., et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Prog Neurobiol. 2001;65(2):135- 172. DOI: 10.1016/S0301-0082(01)00003-X
19. Deacon RM. Measuring motor coordination in mice. J. Vis Exp. 2013(75):e2609. DOI: 10.3791/2609
20. Goes ATR, Jesse CR, Antunes MS, et al. Protective role of chrysin on 6-hydroxydopamine-induced neurodegeneration a mouse model of Parkinson's disease: Involvement of neuroinflammation and neurotrophins. Chem Biol Interact. 2018;279:111- 120. DOI: 10.1016/j.cbi.2017.10.019
21. Brooks SP, Dunnett SB. Tests to assess motor phenotype in mice: a user's guide. Nat Rev Neurosci. 2009;10(7):519-529. DOI: 10.1038/nrn2652
22. Jones BJ, Roberts DJ. The quantiative measurement of motor incoordination in naive mice using an acelerating rotarod. J. Pharm Pharmacol. 1968;20(4):302-304
23. Monville C., Torres EM, Dunnett SB. Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J. Neurosci Methods. 2006;158(2):219-223. DOI: 10.1016/j.jneumeth.2006.06.001
24. Капица И.Г., Кокшенев И.И., Вальдман Е.А., и др. Изучение эффектов инъекционной формы гимантана на экспериментальных моделях паркинсонического синдрома // Фармакокинетика и фармакодинамика. 2012;2(5):10-16.
25. Alvarez-Fischer D., Henze C., Strenzke C., et al. Characterization of the striatal 6-OHDA model of Parkinson's disease in wild type and alpha-synuclein-deleted mice. Exp Neurol. 2008;210(1):182- 193. DOI: 10.1016/j. expneurol.2007.10.012
26. Thornton E., Vink R. Treatment with a substance P. receptor antagonist is neuroprotective in the intrastriatal 6-hydroxydopamine model of early Parkinson's disease. PLoS One. 2012;7(4):e34138. DOI: 10.1371/journal. pone.0034138
27. Morroni F., Tarozzi A., Sita G., et al. Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson's disease. Neurotoxicology. 2013;36:63-71. DOI: 10.1016/j.neuro.2013.03.004.
28. Cuevas J., Rodriguez A., Behensky A., et al. Afobazole modulates microglial function via activation of both sigma-1 and sigma-2 receptors. J. Pharmacol Exp Ther. 2011;339(1):161- 172. DOI: 10.1124/jpet.111.182816
29. Cuevas J., Behensky A., Deng W., et al. Afobazole modulates neuronal response to ischemia and acidosis via activation of sigma-1 receptors. J. Pharmacol Exp Ther. 2011;339(1):152- 160. DOI: 10.1124/jpet.111.182774
30. Francardo V., Bez F., Wieloch T., et al. Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. Brain. 2014;137(Pt 7):1998-2014. DOI: 10.1093/brain/awu107
31. Janda E., Parafati M., Aprigliano S., et al. The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo. Br J. Pharmacol. 2013;168(1):46-59. DOI: 10.1111/j. 1476- 5381.2012.01870.x
Review
For citations:
Kadnikov I.A., Voronin M.V., Seredenin S.B. Afobazole prevents motor function impairment in mice with 6-OHDA induced Parkinsonism. Pharmacokinetics and Pharmacodynamics. 2018;(3):3-8. (In Russ.) https://doi.org/ 10.24411/2587-7836-2018-10017.
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