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

Autor: O. V. Ardashov, Alexander M. Genaev, Arun Kumar Mahato, Yulia Sidorova, Dina V. Korchagina, Alla Pavlova, Georgi E. Salnikov, Tatyana G. Tolstikova, Oksana S. Patrusheva, Konstantin P. Volcho, Nariman F. Salakhutdinov, Ekaterina A. Morozova, N.S. Li-Zhulanov
Přispěvatelé: Institute of Biotechnology
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Parkinson's disease
CYCLOHEX-3-ENE-1
2-DIOL
Physiology
Pharmacology
Biochemistry
chemistry.chemical_compound
Mice
0302 clinical medicine
tyrosine hydroxylase
Glial cell line-derived neurotrophic factor
Cells
Cultured
SELEGILINE
0303 health sciences
biology
DERIVATIVES
MPTP
Dopaminergic
General Medicine
dopamine neurons
GDNF
3. Good health
medicine.anatomical_structure
Neuroprotective Agents
ANIMAL-MODELS
Mitogen-Activated Protein Kinases
medicine.drug
Signal Transduction
Tyrosine 3-Monooxygenase
Cell Survival
Cognitive Neuroscience
Motor Activity
Neuroprotection
03 medical and health sciences
Dopamine
medicine
MANAGEMENT
Animals
MAPK signaling ERK pathway
GFR-ALPHA-1
030304 developmental biology
Tyrosine hydroxylase
RECEPTOR
Dopaminergic Neurons
3112 Neurosciences
MPTP Poisoning
Cell Biology
PROTEIN-KINASE
medicine.disease
Corpus Striatum
chemistry
nervous system
biology.protein
Neuron
neurorestoration
030217 neurology & neurosurgery
NEUROTROPHIC FACTOR
Popis: 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.
Databáze: OpenAIRE
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