Targeting N-methyl-D-aspartate 2B receptor in painful diabetic neuropathy – mechanisms, challenges, and emerging therapeutics

Figure 3 Potential increased release of inflammatory markers from activated glial cells due to prolonged hyperglycaemia. The binding of mediators to their receptors activates Janus kinase 2 (JAK2) and phosphorylates signal transducer and activator of transcription 3 (STAT3). The processes upregulate caveolin-1 (CAV-1) expression and promote N-methyl-D-aspartate receptor-2B (NMDAR-2B) trafficking and activation, increasing calcium ion (Ca²⁺) influx, central sensitisation, and aberrant pain signaling pathway, which leads to the development of diabetic peripheral neuropathy. CaMKII: Calcium-calmodulin-dependent protein kinase II; CREB: Cyclic adenosine monophosphate response element binding protein; IL: Interleukin; SOCS3: Suppressor of cytokine signaling 3; TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor alpha.