PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord

Abstract

BackgroundPyruvate kinase isozymes M2 (PKM2), as a member of pyruvate kinase family, plays a role of glycolytic enzyme in glucose metabolism. It also functions as protein kinase in cell proliferation, signaling, immunity, and gene transcription. In this study, the role of PKM2 in neuropathic pain induced by chronic constriction injury (CCI) was investigated.MethodsRats were randomly grouped to establish CCI models. PKM2, extracellular regulated protein kinases (EKR), p-ERK, signal transducers and activators of transcription (STAT3), p-STAT3, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and p-PI3K/AKT proteins expression in spinal cord was examined by Western blot analysis. Cellular location of PKM2 was examined by immunofluorescence. Knockdown of PKM2 was achieved by intrathecal injection of specific small interfering RNA (siRNA). Von Frey filaments and radiant heat tests were performed to determine mechanical allodynia and thermal hyperalgesia respectively. Lactate and adenosine triphosphate (ATP) contents were measured by specific kits. Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels were detected by ELISA kits.ResultsCCI markedly increased PKM2 level in rat spinal cord. Double immunofluorescent staining showed that PKM2 co-localized with neuron, astrocyte, and microglia. Intrathecal injection of PKM2 siRNA not only attenuated CCI-induced ERK and STAT3 activation, but also attenuated mechanical allodynia and thermal hyperalgesia induced by CCI. However, PKM2 siRNA failed to inhibit the activation of AKT. In addition, PKM2 siRNA significantly suppressed the production of lactate and pro-inflammatory mediators.ConclusionOur findings demonstrate that inhibiting PKM2 expression effectively attenuates CCI-induced neuropathic pain and inflammatory responses in rats, possibly through regulating ERK and STAT3 signaling pathway.

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats

“…This finding is in agreement with previous studies [4849]. Moreover, the current study investigated the possible involvement of ERK phosphorylation in the process of dexmedetomidine analgesia.…”

PKM2: A Potential Regulator of Rheumatoid Arthritis via Glycolytic and Non-Glycolytic Pathways

“…It was found that PKM2 could phosphorylate STAT3 at Tyr705 and promote MEK5 transcriptional activity (46). Inhibition of PKM2 expression could effectively attenuate the neuropathic pain and inflammatory responses induced by CCI in rats, possibly by regulating ERK and STAT3 signaling pathways (47). LPS promoted PKM2 binding to the STAT3 promoter to enhance STAT3 expression and its subsequent nuclear translocation, inducing TNF-α and IL-1β production and cell proliferation in CRC cells (48).…”

Retracted Article: PKM2 overexpression protects against 6-hydroxydopamine-induced cell injury in the PC12 cell model of Parkinson's disease via regulation of the brahma-related gene 1/STAT3 pathway

“…14 It is becoming increasingly evident that PKM2 acts as a glycolytic enzyme and plays signicant roles in glucose metabolism. 15 Moreover, protein kinase PKM2 was involved in cell gene transcription, immunity, signaling and proliferation. 15 Recent evidence has suggested that PKM2 plays a critical role in neurogenesis; 16 however, the function and mechanism of PKM2 in PD is not fully understood.…”