The effect of exogenous melatonin on behavior and oxidative stress indicators in the brain of aging mice with experimental models of nervous system pathology


  • I.F. Labunets State Institute of Genetic and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine, Ukraine
  • N.A. Utko State Institute of Genetic and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine, Ukraine
  • T.N. Panteleymonova State Institute of Genetic and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine, Ukraine
  • G.M. Butenko State Institute of Genetic and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine, Ukraine



neurotoxins MPTP and cuprizone, parkinsonism, demyelination, melatonin, aging, malondialdehyde and antioxidant enzymes in the brain, behavioral reactions


Background. There is a connection between impaired functioning of the nervous system and oxidative stress in Parkinson’s disease and multiple sclerosis. The influence of age on the development of these pathologies was shown, as well as the antioxidant properties of the hormone melatonin. The purpose was to investigate the effect of melatonin administration on the behavior, factors of oxidative stress and antioxidant protection in the brain of aging mice with experimental models of parkinsonism and demyelination. Materials and methods. 129/Sv mice aged 15–16 months received neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 30 mg/kg once, or cuprizone daily with food for 3 weeks. Melatonin was administered at a dose of 1 mg/kg daily at 6 p.m. starting from day 7–8 of toxin exposure. The content of malondialdehyde, the activity of antioxidant enzymes in the brain and behavior parameters were assessed in the open field tests for rigidity and in the rotarod test. Results. The locomotor, emotional and exploratory activities in mice with parkinsonism and demyelination models are lower than those in intact animals. Muscle tone decreases under the influence of cuprizone and increases after MPTP injection; the step length decreases in parkinsonism. Melatonin treatment resulted in increasing the number of squares, step length, and decreasing the retention time on a rotating cylinder in mice with parkinsonism and increasing the number of squares, rea-ring and number of boluses in cuprizone-treated mice. Exogenous melatonin reduces the level of brain malondialdehyde increased by neurotoxins and increases the reduced activity of superoxide dismutase and catalase in mice with parkinsonism, catalase and glutathione peroxidase in mice with demyelination. Conclusions. The positive effects of melatonin on the behavior of aging mice with the MPTP parkinsonism model and the cuprizone model of demyeli-
nation are mediated by increased antioxidant protection in the brain.


Karaban I.N., Karaban N.V., Karasevych N.V. The ways of neuroprotection in Parkinson’s disease. International neurogical journal. 2011. № 6 (44). P. 95-99.

Міщенко Е.С., Шульга О.Д., Бобрик Н.В., Шульга Л.А. Розсіяний склероз: глобальні перспективи. Український медичний часопис. 2014. № 3 (101). С. 84-87.

Guo J.-D., Zhao X., Li Y., Li G.-R., Liu X-L. Damage to dopaminergic neurons by oxidative stress in Parkinson’s disease (Review). Int. J. of molecular medicine. 2018. Vol. 41. P. 1817-1825. doi: 10.3892/ijmm.2018.3406.

Praet J., Guglielmetti C., Berneman Z. Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis. J. Neubiorev. 2014. Vol. 47. P. 485-505.

Labunets I.F., Utko N.A., Savosko S.I., Panteleymonova T.N., Butenko G.M. Changes in nigral neuronal structure, indices of antioxidant protection of the brain and behavior in mice of different age with MPTP parkinsonism model. International neurogical journal. 2020. № 3 (16). P. 7-15. doi: 10.22141/2224-0713.16.3.2020.203444.

Labunets I.F. Possibilities and prospects of the application of the in vivo and in vitro toxic cuprizone model for demyelination in experimental and clinical neurology (literature review and own research results). Ukrainian Neurological Journal. 2018. № 2. P. 63-68. doi: 10.30978/UNZ2018263.

Лабунец И.Ф., Родниченко А.Е. Эффекты мелатонина у молодых и стареющих мышей с токсической купризоновой моделью демиелинизации. Успехи геронтол. 2019. № 3 (32). С. 338-346. PMID: 31512419.

Gutierrer-Valdez A.L., Anaya-Martinez V., Ordonez-Librado J.L., Garcia-Ruiz R., Torres-Esquivel C., Moreno-Rivera M. еt al. Effect of chronic L-Dopa or melatonin treatments after dopamine deafferentation in rats: dyskinesia, motor performance, and cytological analysis. ISRN Neurology. 2012. ID 360379. doi: 10.5402/2012/360379.

Manchester L.C., Coto-Montes A., Boga J.A. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J. Pineal. Res. 2015. № 4 (59). P. 403-419. doi: 10.1111/jpi.12267.

Sarlak G., Jenwitheesuk А., Chetsawang B., Govitrapong P. Effects of melatonin on nervous system aging: neurogenesis and neurodegeneration. J. Pharmacol. Sci. 2013. Vol. 123. P. 9-24. PMID: 23985544.

Wurtman R. Multiple sclerosis, melatonin and neurobehavio-ral diseases. Front. Endocrinol. 2017. 23 October 2017. doi:10.3389/fendo.2017.00280.

Cardinali D.Р. Melatonin: clinical perspectives in neurodegeneration. Front. Endocrinol. 2019. 10. doi: 3389/fendo.2019.00480.

Labunets I.F., Chaikovsky Yu.B., Savosko S.I., Butenko G.M., Sagach V.F., Kop’yak B.S. Effects of melatonin on the behavioral indices and structural characteristics of cerebral and spinal neurons of rats with experimental hemiparkinsonism. Neurophysiology. 2018. № 1 (50). P. 11-22. doi: 10.1007/s11062-018-9712-8.

Muthian G., Mackey V., Prasad K., Chariton C. Curcumin and an antioxidant formulation protect C57Bl/6j mice from MPTP-induced Parkinson’s disease like changes:potential neuroprotection for neurodegeneration. Journal of Parkinsonism and Restless legs syndrome. 2018. Vol. 8. Р. 49-59. doi: 10.2147/JPRLS.S151452.

Uchtyama M., Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal. Biochem. 1978. № 1 (86). P. 271-278. doi: 10.1016/0003-2697(78)90342-1.

Amikishieva A.V. Behavioral phenothyping: up-to date me-thods and equipment. Vestnik VOGiS. 2009. № 3 (13). Р. 529-542.

Fernagut P.O., Diguet E., Labattu B., Tison F. A simple method to measure stride length as an index of nigrostrial dysfunction in mice. J. Neurosci. Methods. 2002. № 2 (113). Р. 123-130. doi: 10.1016/s0165-0270(01)00485-x.

Guo L., Xiong H., Kim J., Wu Y., Laichandani R.R., Cui Y. Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson’s disease. Nat. Neurosci. 2015. № 9 (18). P. 1299-1309. doi: 10.1038/nn.4082.

Mathai A., Ma Y., Pare J.-F., Villalba R.M., Wichmann Th., Smith Y. Reduced cortical innervation of the subthalamic nucleus in MPTP-treated parkinsonian monkeys. Brain. 2015. Vol. 138. P. 946-962. doi: 10.1093/brain/awv018.

Chen D., Zhang T., Lee T.H. Cellular mechanisms of melatonin: insight from neurodegenerative diseases. Biomolecules. 2020. 10. 1158. doi: 10.3390/biom 10081158.

Labunets I.F. Neuroprotective еffects of the pineal hormone melatonin in animals with experimental model of neurodegenerative pathology. Conceptual options for the development of medical science and education. Baltija Bublishing. 2020. P. 355-370. doi: 10.30525/978-9934-588-44-01/18.

Meredith G.E., Rademacher D.J. MPTP mouse models of Parkinson’s disease: an update. J. Parkinsons Dis. 2011. № 1. P. 19-33. doi: 10.3233/JPD-2011-11023.

Vakilzadeh G., Khodagholi F., Ghadin T. The effect of melatonin on behavioral, molecular, and histopathological changes in cuprizone model of demyelination. Mol. Neurobiol. 2016. № 7 (57). P. 4675-4684. doi: 10.1007/s12035-015-9404-y.





Original Researches