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 -