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Abstract <p>KB-R7943 is a selective blocker of the plasma membrane sodium-calciumexchanger (NCX), which regulates the ionic conductance of glutamate NMDAreceptors involved in the pathogenesis of neuropathic pain syndrome.Previously, using an experimental model of diabetes mellitus, weconducted a comprehensive pharmacological investigation of KB-R7943as an effective treatment for neuropathic pain, but the effectsof the therapy on the expression of diabetic neuropathy marker genes werebeyond the scope of our study. The present work was aimed to investigatethe effect of KB-R7943 on the expression of voltage-gated calcium channel(VGCC) genes <i>Cacna2d1</i> (α2δ-1subunit, L-type VGCC) and <i>Cacna1h</i> (α1subunit, T-type VGCC), as well as apoptosis-related genes <i>Bax</i> and <i>Bcl-2</i>,in the hypothalamus, hippocampus, and sensorimotor cortex of ratswith streptozotocin-induced diabetes mellitus. Male Wistar ratswere administered KB-R7943 (10 mg/kg/day) for 1 and 3 weeks. Geneexpression was assessed using real-time PCR. The study demonstratesthat the therapy exerts a complex, region-specific effect on theexpression of key marker genes of diabetic neuropathy in the brain. Thedrug exhibited a pronounced anti-apoptotic effect, with normalizationof the expression ratio of the pro-apoptotic gene <i>Bax</i> to the anti-apoptotic gene <i>Bcl-2</i>, as observed during long-termadministration. KB-R7943 downregulated the mRNA expression of <i>Cacna2d1</i> and <i>Cacna1h</i> genes,whose overexpression plays an important role in the pathogenesisof neuropathic pain and central sensitization. Presumably, by limitingpathological calcium influx, KB-R7943 indirectly normalizes theactivity of calcium-dependent transcription factors, leading tothe suppression of pathological gene expression of VGCCs and pro-apoptoticfactors, while the neuroprotective and antinociceptive effects ofthe drug in diabetic neuropathy are implemented through a multi-levelaction combining direct modulation of NMDA receptor activity withindirect transcriptional remodeling. The obtained results open prospectsfor considering the class of NCX blockers as multi-target therapeuticanalgesic agents.</p>

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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

  • 期刊论文

  • 发表日期：

    2026年4月19日

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  • I. B. Sukhov,
  • M. A. Borodin,
  • N. N. Shestakova

摘要

Abstract

KB-R7943 is a selective blocker of the plasma membrane sodium-calciumexchanger (NCX), which regulates the ionic conductance of glutamate NMDAreceptors involved in the pathogenesis of neuropathic pain syndrome.Previously, using an experimental model of diabetes mellitus, weconducted a comprehensive pharmacological investigation of KB-R7943as an effective treatment for neuropathic pain, but the effectsof the therapy on the expression of diabetic neuropathy marker genes werebeyond the scope of our study. The present work was aimed to investigatethe effect of KB-R7943 on the expression of voltage-gated calcium channel(VGCC) genes Cacna2d1 (α2δ-1subunit, L-type VGCC) and Cacna1h (α1subunit, T-type VGCC), as well as apoptosis-related genes Bax and Bcl-2,in the hypothalamus, hippocampus, and sensorimotor cortex of ratswith streptozotocin-induced diabetes mellitus. Male Wistar ratswere administered KB-R7943 (10 mg/kg/day) for 1 and 3 weeks. Geneexpression was assessed using real-time PCR. The study demonstratesthat the therapy exerts a complex, region-specific effect on theexpression of key marker genes of diabetic neuropathy in the brain. Thedrug exhibited a pronounced anti-apoptotic effect, with normalizationof the expression ratio of the pro-apoptotic gene Bax to the anti-apoptotic gene Bcl-2, as observed during long-termadministration. KB-R7943 downregulated the mRNA expression of Cacna2d1 and Cacna1h genes,whose overexpression plays an important role in the pathogenesisof neuropathic pain and central sensitization. Presumably, by limitingpathological calcium influx, KB-R7943 indirectly normalizes theactivity of calcium-dependent transcription factors, leading tothe suppression of pathological gene expression of VGCCs and pro-apoptoticfactors, while the neuroprotective and antinociceptive effects ofthe drug in diabetic neuropathy are implemented through a multi-levelaction combining direct modulation of NMDA receptor activity withindirect transcriptional remodeling. The obtained results open prospectsfor considering the class of NCX blockers as multi-target therapeuticanalgesic agents.