Amelioration of Parkinson's disease by pharmacological inhibition and knockdown of redox sensitive TRPC5 channels: Focus on mitochondrial health.
Life Sci
; 328: 121871, 2023 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-37352915
ABSTRACT
AIMS:
Transient receptor potential canonical 5 (TRPC5) channels are redox-sensitive cation-permeable channels involved in temperature and mechanical sensation. Increased expression and over-activation of these channels has been implicated in several central nervous system disorders such as epilepsy, depression, traumatic brain injury, anxiety, Huntington's disease and stroke. TRPC5 channel activation causes increased calcium influx which in turn activates numerous downstream signalling pathways involved in the pathophysiology of neurological disorders. Therefore, we hypothesized that pharmacological blockade and knockdown of TRPC5 channels could attenuate the behavioural deficits and molecular changes seen in CNS disease models such as MPTP/MPP+ induced Parkinson's disease (PD). MATERIALS ANDMETHODS:
In the present study, PD was induced after bilateral intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the Sprague Dawley rats. Additionally, SH-SY5Y neurons were exposed to 1-methyl-4-phenylpyridinium (MPP+) to further determine the role of TRPC5 channels in PD. KEYFINDINGS:
We used clemizole hydrochloride, a potent TRPC5 channel blocker, to reverse the behavioural deficits, molecular changes and biochemical parameters in MPTP/MPP+-induced PD. Furthermore, knockdown of TRPC5 expression using siRNA also closely phenocopies these effects. We further observed restoration of tyrosine hydroxylase levels and improved mitochondrial health following clemizole treatment and TRPC5 knockdown. These changes were accompanied by diminished calcium influx, reduced levels of reactive oxygen species and decreased apoptotic signalling in the PD models.SIGNIFICANCE:
These findings collectively suggest that increased expression of TRPC5 channels is a potential risk factor for PD and opens a new therapeutic window for the development of pharmacological agents targeting neurodegeneration and PD.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Canales de Potencial de Receptor Transitorio
/
Neuroblastoma
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Life Sci
Año:
2023
Tipo del documento:
Article
País de afiliación:
India