A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson's Disease

A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson's Disease Научная публикация

Журнал

ACS Chemical Neuroscience
ISSN: 1948-7193

Вых. Данные

Год: 2019, Том: 10, Номер: 10, Страницы: 4337-4349 Страниц : DOI: 10.1021/acschemneuro.9b00396

Ключевые слова

Parkinson's disease; neurorestoration; MAPK signaling ERK pathway; dopamine neurons; tyrosine hydroxylase

Авторы

Ardashov Oleg V. ^1,2 , Pavlova Alla V. ¹ , Mahato Arun Kumar ³ , Sidorova Yulia ³ , Morozova Ekaterina A. ¹ , Korchagina Dina V. ¹ , Salnikov Georgi E. ^1,2 , Genaev Alexander M. ¹ , Patrusheva Oksana S. ¹ , Li-Zhulanov Nikolay S. ^1,2 , Tolstikova Tat'yana G. ¹ , Volcho Konstantin P. ^1,2 , Salakhutdinov Nariman. F. ^1,2

Организации

1	(Данные Web of science) Russian Acad Sci, NN Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, Lavrentiev Ave 9, Novosibirsk 630090, Russia
2	(Данные Web of science) Novosibirsk State Univ, Pirogova 2, Novosibirsk 630090, Russia
3	(Данные Web of science) Univ Helsinki, HiLIFe, Inst Biotechnol, Lab Mol Neurosci, Viikinkaari 5D, FIN-00014 Helsinki, Finland

We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.

Ardashov O.V. , Pavlova A.V. , Mahato A.K. , Sidorova Y. , Morozova E.A. , Korchagina D.V. , Salnikov G.E. , Genaev A.M. , Patrusheva O.S. , Li-Zhulanov N.S. , Tolstikova T.G. , Volcho K.P. , Salakhutdinov N.F.
A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson's Disease

ACS Chemical Neuroscience. 2019. V.10. N10. P.4337-4349. DOI: 10.1021/acschemneuro.9b00396 WOS Scopus РИНЦ

Полный текст от издателя

Опубликована online:	29 авг. 2019 г.
Опубликована в печати:	16 окт. 2019 г.

Web of science	WOS:000491219000017
Scopus	2-s2.0-85073314057
РИНЦ	41697427
OpenAlex	W2970927689