We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects.
- Authors
Nagib, Marwa M.; Zhang, Sicheng; Yasmen, Nelufar; Li, Lexiao; Hou, Ruida; Yu, Ying; Boda, Vijay K.; Wu, Zhongzhi; Li, Wei; Jiang, Jianxiong
- Abstract
Objective: As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine‐induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 only provides limited benefits in pilocarpine‐treated mice, likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW‐65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW‐65 on seizure susceptibility. Methods: We first examined the pharmacokinetic properties including plasma half‐life and brain to plasma ratio of JW‐65 after systemic administration in mice. We then investigated the effects of TRPC3 inhibition by JW‐65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW‐65‐treated mice to pentylenetetrazole (PTZ)‐induced seizures with phenytoin as a comparator. Results: JW‐65 showed adequate half‐life and brain penetration in mice, justifying its use for central nervous system conditions. Systemic treatment with JW‐65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW‐65 was administered after pilocarpine‐induced behavioral seizures were well established and was confirmed by time‐locked electroencephalographic monitoring and synchronized video. Moreover, JW‐65‐treated mice showed substantially decreased susceptibility to PTZ‐induced seizures in a dose‐dependent manner. Significance: These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW‐65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this proof‐of‐concept study establishes TRPC3 as a novel feasible therapeutic target for the treatment of some forms of epilepsy.
- Subjects
PYRAZOLES; TRP channels
- Publication
Epilepsia (Series 4), 2022, Vol 63, Issue 4, p1003
- ISSN
0013-9580
- Publication type
Article
- DOI
10.1111/epi.17190