Taselisib, a PI3K Inhibitor, Alleviates Neuropathic Pain through HIF-1α-Mediated Angiogenesis in a Rat Model of Chronic Constriction Injury.

Abstract

Introduction: Neuropathic pain is associated with hypoxia, inflammation, and metabolic dysregulation, in which hypoxia-inducible factor-1α (HIF-1α) plays a key regulatory role. This study investigates whether phosphoinositide 3-kinase (PI3K) inhibition by taselisib alleviates neuropathic pain via suppression of HIF-1α-mediated pathological signaling.

Methods: In this study, a rat model of chronic constriction injury (CCI) was used to investigate whether neuropathic pain could be alleviated by taselisib, a selective PI3K inhibitor. Taselisib was administered daily, with or without co-administration of dimethyloxalylglycine (DMOG), a HIF-1α activator. Mechanical allodynia and thermal hyperalgesia were evaluated using behavioral tests. mRNA level in the dorsal root ganglia (DRG) was quantified by RT-qPCR, whereas protein levels were assessed by Western blotting, immunofluorescence, and metabolic assays were performed to assess angiogenesis, glycolytic activity, and inflammatory responses.

Results: Taselisib significantly alleviated mechanical allodynia and thermal hyperalgesia in CCI rats, effects that were attenuated by co-administration of the HIF-1α activator DMOG. Taselisib suppressed CCI-induced upregulation of HIF-1α in DRG at both transcript and protein levels, and this suppression was reversed by DMOG. Downstream targets of HIF-1α, including mTOR, VEGFA, GLUT1, PFKM, and PDK1, were similarly downregulated by taselisib and partially restored upon HIF-1α activation. Metabolically, taselisib reduced lactate accumulation and restored ATP levels, indicating inhibition of glycolytic reprogramming. Taselisib also attenuated systemic and DRG-localized inflammatory responses, including IL-6, IL-1β, and NF-κB p65 expression; these anti-inflammatory effects were mitigated by DMOG.

Conclusion: Taselisib alleviates neuropathic pain by disrupting HIF-1α-mediated angiogenic, inflammatory, and metabolic signaling. Targeting the PI3K-HIF-1α axis offers a promising therapeutic approach.