Pyk2 dysregulation in temporal lobe epilepsy: insights from human resected tissues and pharmacological modulation in a rodent model.

Abstract

Temporal lobe epilepsy (TLE) is a common and often drug-resistant neurological disorder, presenting a major clinical challenge due to the limited effectiveness of current therapies. There is a pressing need to identify novel molecular targets to improve treatment outcomes. This study focuses on Pyk2, a calcium-sensitive non-receptor tyrosine kinase implicated in neuronal signalling and excitability. Given its abundant neural expression and synaptic role, the research investigates Pyk2's spatio-temporal activity and phosphorylation in mesial TLE (MTLE) patients and in a lithium-pilocarpine rat model across acute and chronic stages. Using techniques such as western blotting, qRT-PCR, kinase assays, and FACS, the study also explores the impact of PF-4,618,433, a pharmacological Pyk2 inhibitor. Elevated phosphorylation of Pyk2 at Tyr402 was observed in MTLE patient hippocampi and temporal lobes, correlating with increased intracellular calcium. In rats, Pyk2 activation displayed stage- and region-specific changes, notably extending to cortical areas in chronic TLE. Inhibition of Pyk2 reduced its activity, significantly lowering seizure frequency and intensity. These findings suggest that calcium-driven, temporally regulated Pyk2 activation contributes to TLE pathology. Targeting Pyk2 may represent a promising therapeutic strategy, offering potential for seizure mitigation and network remodeling. Further research is needed to assess long-term effects and refine clinical applications.