Metformin attenuates HSV-1-induced neuropathic pain by restoring Sirt3-mediated mitophagy

Varicella-zoster virus reactivation causes neuroinflammation and post-herpetic neuralgia (PHN), in which the mechanism needs to be further explored. Given that Herpes simplex virus type 1 (HSV-1) infection induces a similar neuropathological process, a corresponding model was established for this study. Here we reported that Sirt3 expression decreased in spinal dorsal horn and microglia upon HSV-1 infection-induced neuropathic pain model, which was accompanied by increased mitochondria ROS and disrupted mitophagy. Sirt3 deficiency inhibited the anti-viral innate immunity responses, increased viral loads and mitochondrial ROS production, disrupted mitophagy both in vivo and in vitro. Sirt3 knockdown replicated the cellular responses, while Sirt3 overexpression enhanced the antiviral innate immunity in microglia. Mechanism research revealed that HSV-1 infection disrupted CREB-mediated Sirt3 transcription. AMPK agonist metformin treatment could increase CREB-mediated Sirt3 transcription and enhance anti-viral innate immunity both in vitro and in vivo. In sum, our study reveals the inhibition of CREB-mediated Sirt3 transcription might be the pathology of HSV-1-induced neuropathic pain, which can be blocked by metformin.