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

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

Результат исследования: Научные публикации в периодических изданияхстатья

1 Цитирования (Scopus)

Аннотация

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.

Язык оригиналаанглийский
Страницы (с-по)4337-4349
Число страниц13
ЖурналACS chemical neuroscience
Том10
Номер выпуска10
DOI
СостояниеОпубликовано - 16 окт 2019

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