SIRT3 is required for the protective function of ketogenic diet on neural inflammation and neuropathic pain

Chronic neural inflammation is the key pathology of neuropathic pain. The ketogenic diet (KD) has been shown to reduce neural inflammation and hyperexcitability in Alzheimer's disease. However, the function and mechanism of KD in neuropathic pain remains unclear. In this study, we first found that the KD production was decreased upon neuropathic pain induced by chronic constriction injury (CCI). Then we demonstrated that KD effectively alleviated CCI-induced thermal hyperalgesia and mechanical allodynia and relieved neuroinflammation by reducing microglia activation and pro-inflammatory cytokines. β-hydroxybutyrate (BHB), a major component of KD, reduced ROS production by enhancing mitochondrial membrane potential in microglia, thereby decreasing microglia-induced inflammatory responses. In vivo and in vitro experiments revealed that the expression of UCP2, SIRT3 and PGC-1α expression in the spinal dorsal horn was increased by KD. SIRT3-deficiency abolished the protective function of KD on neuropathic pain. Additionally, SIRT3 deficiency decreased BHB production due to the reduced expression of ketone body synthases in the liver and ketone body-utilizing enzymes in the spinal dorsal horn. These findings suggest that SIRT3 is a promising therapeutic target for neuropathic pain, particularly in the context of a ketogenic diet, which may inspire novel therapeutic strategies and potentially improve patient prognosis and quality of life.