Sirtuin 1 Is a Potential Target for the Treatment of Neurogenic Intermittent Claudication by Modulating Pyroptosis

Abstract

Neurogenic intermittent claudication (NIC) pathogenesis associated with lumbar spinal stenosis (LSS) remains unclear. However, pyroptosis has been implicated in the pathogenesis of various central nervous system disorders. Therefore, the present study aimed to explore the potential role of pyroptosis in NIC progression. Additionally, the present study investigated the possible involvement of Sirtuin 1 (Sirt1), a protein recognized for its neuroprotective properties, in mitigating the progression of NIC by alleviating pyroptosis. In the current study, a rat model of NIC associated with LSS was successfully constructed by inserting a silicone strip into the vertebral plates. The Basso Beattie Bresnahan score was employed to assess the motor function of rats. Western blot analysis was performed to measure the levels of pyroptosis-related proteins in rat spinal cord tissue. Meanwhile, PC-12 cells were cultured with H₂O₂ to establish an in vitro model of oxidative stress, allowing to investigate the effects of Sirt1 on cell pyroptosis and oxidative stress in H₂O₂-treated cells. The current results showed that rats with NIC developed both motor and sensory dysfunction. Additionally, NIC surgery notably elevated NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), gasdermin D N-terminal (GSDMD-N), and IL-1β levels in the spinal cord tissues of rats, suggesting that pyroptosis is activated in the context of NIC. Significantly, downregulation of Sirt1 exacerbated malondialdehyde and reactive oxygen species levels, and simultaneously reduced GSH levels in H₂O₂-stimulated PC-12 cells, suggesting that Sirt1 deficiency can aggravate oxidative stress. Meanwhile, downregulation of Sirt1 also led to increased levels of NLRP3, ASC, GSDMD-N, and cleaved caspase 1 in H₂O₂-stimulated PC-12 cells, suggesting that Sirt1 deficiency can further enhance the pyroptosis in these cells. Targeting pyroptosis signaling may yield new insights into the treatment of NIC. The mechanisms mediated by pyroptosis could offer valuable perspectives on the pathogenesis and management of this condition.