Traumatic brain injury is a global leading cause of disability and death, which puts patients at high risk for developing dementia. Early intervention is believed as the key to minimize the development of brain damages that could aggravate the symptoms. Here, we report that the serine protease inhibitor SerpinA3N is upregulated in hippocampal neurons in the early stage of hippocampal stab injury (HSI), while its deficiency causes a greater degree of neuronal apoptosis and severer impairments of spatial learning and memory in mice after HSI. We further show that MMP2 is a key substrate of SerpinA3N, and MMP2 specific inhibitor (ARP100) can protect against neuronal apoptosis and cognitive dysfunction in mice after HSI. These findings demonstrate a critical role for SerpinA3N in neuroprotection, suggesting that SerpinA3N and MMP2 inhibitors might be a novel therapeutic agents for neurotrauma.

创伤性脑损伤是全球导致残疾和死亡的主要原因，这使患者面临患痴呆症的高风险。早期干预被认为是最大程度地减少可能加重症状的脑损伤发展的关键。在此，我们报道丝氨酸蛋白酶抑制剂SerpinA3N在海马刺伤（HSI）早期在海马神经元中表达上调，而其缺乏会导致HSI后小鼠更大程度的神经元凋亡和更严重的空间学习和记忆损伤。我们进一步表明，MMP2 是 SerpinA3N 的关键底物，MMP2 特异性抑制剂 (ARP100) 可以防止 HSI 后小鼠的神经元凋亡和认知功能障碍。这些发现证明了 SerpinA3N 在神经保护中的关键作用，表明 SerpinA3N 和 MMP2 抑制剂可能是神经创伤的新型治疗药物。