The Potential Role of Glycogen Synthase Kinase-3β in Neuropathy-Induced Apoptosis in Spinal Cord

Introduction: Glycogen Synthase Kinase-3β (GSK-3β) participates in several signaling pathways and plays a crucial role in neurodegenerative diseases, inflammation, and neuropathic pain. The ratio of phosphorylated GSK-3β over total GSK-3β (p-GSK-3β/t-GSK-3β) is reduced following nerve injury. Apoptosis is a hallmark of many neuronal dysfunctions in the context of neuropathic pain. Thus, this study aimed to evaluate the contribution of p-GSK-3β/t-GSK-3β ratio in spinal dorsal horn apoptosis following peripheral nerve injury.  Methods: In this study, adult male Wistar rats (220-250 g) underwent Spinal Nerve Ligation (SNL) surgery. Mechanical allodynia and thermal hyperalgesia were assessed before the surgery (day 0); then, every other day up to day 8. GSK-3β selective inhibitor, AR-014418 [0.3 mg/kg, Intraperitoneal (IP)] was administrated 1 h prior to SNL on day 0, then daily up to the day 8. The GSK-3β activity and apoptosis in the lumbar section (L4, L5, or L6) of the study rat’s spinal cord were assessed by immunohistochemical and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining, respectively on day 8 post-SNL.  Results: Following the SNL, the mechanical allodynia and thermal hyperalgesia increased on day 2 up to day 8 post-SNL. The ratio of p-GSK-3β/t-GSK-3β decreased, and the number of apoptotic cells increased in the spinal dorsal horn on day 8. However, AR-A014418 administration could increase the p-GSK-3β/t-GSK-3β ratio and decreased apoptosis in the SNL rats. In addition, AR-A014418 decreased the mechanical allodynia from day 4 up to day 8; however, it did not affect thermal hyperalgesia.  Conclusion: The study findings suggested that increasing the p-GSK-3β/t-GSK-3β ratio might be a helpful strategy for reducing the apoptotic cells and subsequent neuropathic pain during peripheral nerve injury.