Effect of Orally Administered Sodium-Calcium Exchanger Blocker KB-R7943 with an Analgesic Efficacy on the Expression of Diabetic Neuropathy Marker Genes in the Hypothalamus, Hippocampus, and Sensorimotor Cortex of Rats with Streptozotocin-Induced Diabetes

KB-R7943 is a selective blocker of the plasma membrane sodium-calcium exchanger (NCX), which regulates the ionic conductance of glutamate NMDA receptors involved in the pathogenesis of neuropathic pain syndrome. Previously, using an experimental model of diabetes mellitus, we conducted a comprehensive pharmacological investigation of KB-R7943 as an effective treatment for neuropathic pain, but the effects of the therapy on the expression of diabetic neuropathy marker genes were beyond the scope of our study. The present work was aimed to investigate the effect of KB-R7943 on the expression of voltage-gated calcium channel (VGCC) genes Cacna2d1 (α2δ-1 subunit, L-type VGCC) and Cacna1h (α1 subunit, T-type VGCC), as well as apoptosis-related genes Bax and Bcl-2, in the hypothalamus, hippocampus, and sensorimotor cortex of rats with streptozotocin-induced diabetes mellitus. Male Wistar rats were administered KB-R7943 (10 mg/kg/day) for 1 and 3 weeks. Gene expression was assessed using real-time PCR. The study demonstrates that the therapy exerts a complex, region-specific effect on the expression of key marker genes of diabetic neuropathy in the brain. The drug exhibited a pronounced anti-apoptotic effect, with normalization of the expression ratio of the pro-apoptotic gene Bax to the anti-apoptotic gene Bcl-2, as observed during long-term administration. KB-R7943 downregulated the mRNA expression of Cacna2d1 and Cacna1h genes, whose overexpression plays an important role in the pathogenesis of neuropathic pain and central sensitization. Presumably, by limiting pathological calcium influx, KB-R7943 indirectly normalizes the activity of calcium-dependent transcription factors, leading to the suppression of pathological gene expression of VGCCs and pro-apoptotic factors, while the neuroprotective and antinociceptive effects of the drug in diabetic neuropathy are implemented through a multi-level action combining direct modulation of NMDA receptor activity with indirect transcriptional remodeling. The obtained results open prospects for considering the class of NCX blockers as multi-target therapeutic analgesic agents.