Neuroprotective Potential of HC070, a Potent TRPC5 Channel Inhibitor in Parkinson's Disease Models: A Behavioral and Mechanistic Study.

Abstract

Transient receptor potential canonical 5 (TRPC5) channels are predominantly expressed in the striatum and substantia nigra of the brain. These channels are permeable to calcium ions and are activated by oxidative stress. The physiological involvement of TRPC5 channels in temperature and mechanical sensation is well documented; however, evidence for their involvement in the pathophysiology of neurodegenerative disorders like Parkinson's disease (PD) is sparse. Thus, in the present study, the role of TRPC5 channels and their associated downstream signaling was elucidated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+) model of PD. Bilateral intranigral administration of MPTP and 24 h MPP+ exposure were performed to induce PD in the Sprague-Dawley rats and SH-SY5Y cells, respectively. MPTP led to behavioral anomalies and TRPC5 overexpression accompanied by increased calcium influx, apoptosis, oxidative stress, and mitochondrial dysfunctions. In addition, tyrosine hydroxylase (TH) expression was significantly lower in the midbrain and substantia nigra compared to sham animals. Intraperitoneal administration of potent and selective TRPC5 inhibitor, HC070 (0.1 and 0.3 mg/kg) reversed the cognitive and motor deficits seen in MPTP-lesioned rats. It also restored the TH and TRPC5 expression both in the striatum and midbrain. Furthermore, in vitro and in vivo studies suggested improvements in mitochondrial health along with reduced oxidative stress, apoptosis, and calcium-mediated excitotoxicity. Together, these results showed that inhibition of TRPC5 channels plays a crucial part in the reversal of pathology in the MPTP/MPP+ model of Parkinson's disease.