The role of peptidase neurolysin in neuroprotection and neural repair after stroke.

Current experimental stroke research has evolved to focus on detailed understanding of the brain’s self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin (Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic (bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective (angiotensin-(1–7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the (sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.

当前的实验性卒中研究已经发展到侧重于详细了解大脑的自我保护和修复机制，并利用这些知识开发新的疗法。在此背景下，肽酶和神经肽的作用越来越受到关注。在这篇重点综述中，简要讨论了肽酶神经溶素（Nln）及其细胞外肽底物与缺血性卒中病理生理学的关系。卒中后Nln的上调被视为卒中急性期的一种代偿性脑保护机制，因为被Nln灭活的主要神经肽具有神经/脑毒性（缓激肽、P物质、神经降压素、血管紧张素II、血啡肽），而Nln产生的肽具有神经/脑保护作用（血管紧张素 - (1 - 7)、亮氨酸 - /甲硫氨酸 - 脑啡肽）。这一观点得到了实验研究的证实，这些研究记录了卒中后抑制Nln会使小鼠的卒中结果恶化，而在大脑中过表达Nln的小鼠卒中结果则显著改善。Nln在卒中（亚）慢性期的作用不太明确，并且很可能这种肽酶在神经修复机制中没有主要作用。这是因为Nln的底物在向一个方向调节神经修复机制方面不太一致，有些似乎具有增强/刺激神经修复的潜力，而其他则相反。未来专注于Nln在卒中病理生理学中作用的研究应该确定其作为卒中治疗的脑保护靶点的潜力，因为其调节多个与脑损伤机制密切相关的神经肽系统的独特能力可能比调节卒中药物治疗的一种致病途径更具优势。