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

Show full item record



Permalink

http://hdl.handle.net/10138/322044

Citation

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 2019 , ' 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 , vol. 10 , no. 10 , pp. 4337-4349 . https://doi.org/10.1021/acschemneuro.9b00396

Title: 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
Author: Ardashov, Oleg V.; Pavlova, Alla V.; Mahato, Arun Kumar; Sidorova, Yulia; Morozova, Ekaterina A.; Korchagina, Dina V.; Salnikov, Georgi E.; Genaev, Alexander M.; Patrusheva, Oksana S.; Li-Zhulanov, Nikolay S.; Tolstikova, Tat'yana G.; Volcho, Konstantin P.; Salakhutdinov, Nariman. F.
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2019-10
Language: eng
Number of pages: 25
Belongs to series: ACS chemical neuroscience
ISSN: 1948-7193
URI: http://hdl.handle.net/10138/322044
Abstract: 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.
Subject: Parkinson's disease
neurorestoration
MAPK signaling ERK pathway
dopamine neurons
tyrosine hydroxylase
NEUROTROPHIC FACTOR
PROTEIN-KINASE
ANIMAL-MODELS
GDNF
DERIVATIVES
RECEPTOR
CYCLOHEX-3-ENE-1,2-DIOL
GFR-ALPHA-1
SELEGILINE
MANAGEMENT
3112 Neurosciences
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
DE_Manuscript_Corr_003_002_YS.pdf 1.602Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record