Research output: Contribution to journal › Article › peer-review
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. / Ardashov, Oleg V.; Pavlova, Alla V.; Mahato, Arun Kumar et al.
In: ACS chemical neuroscience, Vol. 10, No. 10, 16.10.2019, p. 4337-4349.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - 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
AU - Ardashov, Oleg V.
AU - Pavlova, Alla V.
AU - Mahato, Arun Kumar
AU - Sidorova, Yulia
AU - Morozova, Ekaterina A.
AU - Korchagina, Dina V.
AU - Salnikov, Georgi E.
AU - Genaev, Alexander M.
AU - Patrusheva, Oksana S.
AU - Li-Zhulanov, Nikolay S.
AU - Tolstikova, Tat'yana G.
AU - Volcho, Konstantin P.
AU - Salakhutdinov, Nariman F.
N1 - Publisher Copyright: © 2019 American Chemical Society. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/10/16
Y1 - 2019/10/16
N2 - 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.
AB - 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.
KW - dopamine neurons
KW - ERK pathway
KW - MAPK signaling
KW - neurorestoration
KW - Parkinson’s disease
KW - tyrosine hydroxylase
KW - Parkinson's disease
KW - MANAGEMENT
KW - NEUROTROPHIC FACTOR
KW - PROTEIN-KINASE
KW - RECEPTOR
KW - MAPK signaling ERK pathway
KW - GDNF
KW - ANIMAL-MODELS
KW - SELEGILINE
KW - GFR-ALPHA-1
KW - DERIVATIVES
KW - CYCLOHEX-3-ENE-1,2-DIOL
KW - Cell Survival/drug effects
KW - Corpus Striatum/drug effects
KW - Dopaminergic Neurons/cytology
KW - Motor Activity/drug effects
KW - Tyrosine 3-Monooxygenase/metabolism
KW - Cells, Cultured
KW - Neuroprotective Agents/pharmacology
KW - Signal Transduction/drug effects
KW - Animals
KW - MPTP Poisoning/drug therapy
KW - Mitogen-Activated Protein Kinases/metabolism
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85073314057&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.9b00396
DO - 10.1021/acschemneuro.9b00396
M3 - Article
C2 - 31464415
AN - SCOPUS:85073314057
VL - 10
SP - 4337
EP - 4349
JO - ACS chemical neuroscience
JF - ACS chemical neuroscience
SN - 1948-7193
IS - 10
ER -
ID: 21857422