Intrathecal lactate dehydrogenase A inhibitors FX11 and oxamate alleviate chronic constriction injury-induced nociceptive sensitization through neuroinflammation and angiogenesis

Abstract

BACKGROUND: Neuropathic pain involves neuroinflammation and upregulation of glycolysis in the central nervous system. Unfortunately, few effective treatments are available for managing this type of pain. The overactivation of lactate dehydrogenase A (LDHA), an essential enzyme in glycolysis, can cause neuroinflammation and nociception. This study investigated the spinal role of LDHA in neuropathic pain. METHOD: Using immunohistochemical analysis, nociceptive behavior, and western blotting, we evaluated the cellular mechanisms of intrathecal administration of LDHA inhibitors, including FX11 and oxamate, in chronic constriction injury (CCI)-induced neuropathic rats. RESULT: FX11 and oxamate attenuated CCI-induced neuronal LDHA upregulation and nociceptive sensitization. Moreover, CCI-induced neuroinflammation, microglial polarization, and angiogenesis were attenuated by LDHA inhibitors. These inhibitors regulate the TANK binding kinase-1 (TBK1)/hypoxia-inducible factor 1 subunit alpha (HIF-1α) axis, crucial for controlling inflammation and new blood vessel growth. Additionally, CCI-induced nuclear LDHA translocation, as associated with oxidative stress resistance, was attenuated by LDHA inhibitors. CONCLUSION: In conclusion, LDHA may be a potential therapeutic target for treating neuropathic pain by regulating neuroinflammation and angiogenesis.