Taselisib, a PI3K inhibitor, alleviates neuropathic pain through HIF-1a-mediated angiogenesis in a rat model of chronic constriction injury.

BACKGROUND

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

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 quantitative real-time PCR, 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.