Characterization of TRPV2-associated pathology in Parkinson's disease and therapeutic modulation using Tranilast.

Abstract

Introduction: Transient Receptor Potential (TRP) channels have gained worldwide attention for their expression and distribution in multiple human organs. Among these TRPs, Transient Receptor Potential Vanilloid (TRPV) channels play diverse physiological roles in the brain, and changes in their expression contribute to central nervous system (CNS) diseases. In a previous druggable-genome α-synuclein modifier screen, a member of the TRPV family, TRPV2, emerged as a Tier 3 ion-channel candidate, meeting directionality and conflict-score criteria, though with limited shRNA-level support. However, based on this preliminary data and the known role of TRPV2 in Ca²⁺ entry and cellular stress responses, we decided to investigate its role in detail using experimental PD models.

Methods: In the present investigation, 6-hydroxydopamine (6-OHDA) was used in vivo (Sprague Dawley rats) and in vitro (SH-SY5Y cells) to induce Parkinson's disease (PD), and its effect on TRPV2 expression was investigated. The study further involved measuring behavioral parameters using the rotarod, open field, apomorphine, and cylinder tests.

Results: 6-OHDA administration induced excessive reactive oxygen species (ROS) production and increased expression of TRPV2 channels. This is also accompanied by increased intracellular calcium influx and reduces cell viability. However, Tranilast, a TRPV2 antagonist, exhibited promising neuroprotective effects in the 6-OHDA PD model by restoring tyrosine hydroxylase levels, reducing oxidative stress, and improving motor function. Also, it diminished the intracellular Ca²⁺ influx and reduced ROS levels in the 6-OHDA-treated SH-SY5Y cells.

Conclusion: Overall, our results suggest that TRPV2 levels are elevated in PD, and targeting TRPV2 could be a potential therapeutic approach in the future.