Abstract：
Spinal Cord Injury (SCI) is a debilitating disease associated with a significant economic burden owing to its high level of disability; however, current treatment options have only limited efficacy. Past research has shown that iron-dependent programmed cell death, also known as ferroptosis, plays a critical role in the pathogenesis of SCI. The sigma-1 receptor (Sig-1R) is widely distributed in the central nervous system, and has been implicated in the pathophysiology of several neurological and psychiatric disorders. Several in vivo and ex vivo studies have shown that Sig-1R activation exerts unique neuroprotective effects. However, the underlying mechanisms remain unclear. To date, no study has yet demonstrated the association between Sig-1R activation and ferroptosis in patients with SCI. However, the present study found that Sig-1R activation effectively promoted the recovery of motor function in mice after spinal cord injury, attenuated neuronal apoptosis, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited ferroptosis in spinal cord tissues following SCI in mice. Ferroptosis and IRE1α were significantly upregulated after spinal cord injury, while sigma-1 receptor agonists were able to facilitate this result through the elimination of inositol-requiring enzyme-1 alpha (IRE1α)-mediated neuronal ferroptosis. Therefore, sigma-1 receptor activation could attenuate ferroptosis after SCI by reducing IRE1α and improving functional recovery after SCI, potentially representing a new therapeutic strategy for treating SCI.
摘要：
脊髓损伤（SCI）是一种使人衰弱的疾病，由于其严重的残疾而导致严重的经济负担；然而，目前的治疗选择只有有限的疗效。过去的研究表明，铁依赖的程序性细胞死亡，也被称为铁中毒，在SCI的发病机制中起着至关重要的作用。sigma-1受体(Sig-1R)广泛分布于中枢神经系统,并与几种神经和精神疾病的病理生理学有关。一些体内和离体研究表明Sig-1R活化发挥独特的神经保护作用。然而,潜在机制尚不清楚.迄今为止,尚未有研究证明SCI患者中Sig-1R激活与铁凋亡之间存在关联.然而,本研究发现Sig-1R激活能有效促进脊髓损伤后小鼠运动功能的恢复,神经元凋亡减弱，减少促炎细胞因子的产生和铁的积累，并抑制SCI小鼠脊髓组织中的铁性下垂。脊髓损伤后铁性凋亡和IRE1α显著上调，而sigma-1受体激动剂能够通过消除需要肌醇的酶-1α（IRE1α）介导的神经元铁凋亡来促进这一结果。因此,sigma-1受体激活可以通过减少IRE1α和改善SCI后功能恢复来减轻SCI后的铁死亡，这可能是治疗SCI的新治疗策略。
