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

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.

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.

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.

In conclusion, LDHA may be a potential therapeutic target for treating neuropathic pain by regulating neuroinflammation and angiogenesis.