Sirtuin1 in Spinal Cord Injury: Regulatory Mechanisms, Microenvironment Remodeling and Therapeutic Potential

Spinal cord injury (SCI) is a complex central nervous system disorder characterized by multifaceted pathological processes. Sirtuin 1 (Sirt1) has emerged as a promising therapeutic target for SCI repair due to its potential to protect neurons, regulate glial and vascular cells, and optimize the injury microenvironment. Sirt1 is a NAD+-­dependent deacetylase known for its broad regulatory functions in cellular processes such as inflammation, oxidative stress, autophagy, metabolism, and mitochondrial function. Sirt1 plays a multifaceted role in the repair process following SCI. Sirt1 serves a crucial neuroprotective function in spinal cord injury (SCI), impacting a wide array of neural cell types. The multiple regulatory effects of Sirt1 not only contribute to restore neurological function, but also enhance the overall repair potential of SCI.

• 1
  Sirt1 exerts broad regulatory effects across diverse pathological processes and cell types post-­SCI. It promotes neuronal survival and axonal regeneration, modulates astrocytes and microglia to resolve inflammation, supports oligodendrocyte-­mediated myelination, and enhances vascular endothelial function.
• 2
  Sirt1 regulates multiple pathways through its deacetylase activity, thereby inhibiting apoptosis. Research has indicated that melatonin inhibits neuronal apoptosis and activates autophagy after SCI by upregulating the Sirt1-­mediated AMPK pathway, thereby providing neuroprotection.
• 3
  Sirt1 is pivotal in upholding the structural and functional integrity of both blood–brain barrier (BBB) and BSCB. The molecular mechanisms underlying BSCB disruption after SCI involve a complex cascade of events. Studies have shown that the activation of Sirt1 deacetylates and stabilizes key tight junction proteins including ZO-­1, occludin, and claudin-­5, helping maintain their proper localization and function.