Reactive nitrogen species: dual roles for blood brain barrier disruption and brain repairs in cerebral ischemia and reperfusion injury

Abstract

Free radicals play an important role in cerebral ischemia-reperfusion injury. Cerebral ischemia and reperfusion insults induce the production and accumulation of free radicals and trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and cell death. As an important component of free radicals, reactive nitrogen species (RNS), such as nitric oxide (NO) and peroxynitrite (ONOO ), is critical player in the process of cerebral ischemia-reperfusion injury. Activation of matrix metalloproteinases (MMPs) mediated by RNS is one of the key steps in BBB opening. As proteolytic zinc-containing enzymes, MMPs induce the degradation of the extracellular matrix around cerebral blood vessels and neurons. Both NO and ONOO－ can activate MMPs and degrade tight junctions (TJs), leading to BBB breakdown in cerebral ischemia-reperfusion injury. On the other hand, recent progress indicates that RNS also participate in the regulations of spontaneous neurogenesis and brain repair in post-ischemic brains. It is of interesting why and how such small and short lifetime species have the complex biological activites on mediating BBB disruption as well as regulating neurogenesis. Caveolin-1, a membrane integral protein located at caveolae, appears to be a key player in the process. Caveolin-1 can protect BBB integrity through inhibiting MMPs activation, but inhibit neural differentiation of neural progenitor/stem cells through regulating multiple cell growth signaling pathways. NO could down-regulate caveolin-1 whereas the down-regulation of caveolin-1 subsequently induce the increase of NOS activity and produce more NO in the ischemic brains. The interaction of RNS and caveolin-1 forms a positive feedback loop through MMP activations, which provides amplified impacts on BBB dysfunction during cerebral ischemia-reperfusion injury. RNS production also potentially regulates neurogenesis through interacting with caveolin-1 and other cell signaling mechanisms. Herewith, we reviewed the recent progress in the roles of RNS on BBB permeability and neurogenesis. In conclusion, RNS can be a cytotoxic factor as well as neurogenesis signaling. The neurotoxicity or neurogenesis properties of RNS depend on the amount of RNS production in neurons, endothelial cells and their microenvironment during cerebral ischemia-reperfusion injury.

在脑缺血再灌注损伤中， 自由基发挥着重要作用。脑缺血及再灌注可产生大量的自由基， 随着这些自由基的聚集， 会引发一系列的分子级联反应， 从而增加血脑屏障的通透性， 诱发脑水肿、 出血、 炎症反应及细 胞死亡。 以一氧化氮（NO）及过氧亚硝基阴离子（ONOO－）为代表的活性氮（reactive nitrogen species， RNS）， 是自由基的重要组成部分， 它们在脑缺血再灌注损伤中作用显著。 一方面， 活性氮能激活基质金属蛋 酶（MMPs）， 破坏血脑屏障。 MMPs作为一大类含2价锌离子的水解酶， 其激活可以降解脑血管及神经元细胞外基质。 脑缺血再灌注损伤产生NO和ONOO－， 它们均可以通过激活MMPs， 降解紧密连接蛋白， 从而破坏血脑屏障。 另一方面， 近期研究发现， 活性氮也参与了脑缺血后神经再生及修复的调节过程。 因此， 了解这些活性小分子在血脑屏障破坏及神经再生中的复杂生物活性将很有意义。 小窝蛋白1（Caveolin-1）就是活性氮自由基的重要靶分子， 它是一种细胞表面的穴样内陷（caveolae）中的膜蛋白， 可以通过抑制MMPs的激活保护血脑屏障的完整性。 下调Caveolin-1的表达将引起血脑屏障的破坏。 脑缺血所产生的NO能下调Caveolin-1 的表达， 而Caveolin-1 的下调， 能引起NO合酶的增加， 促进生成更多的NO。 活性氮与Caveolin-1互相作用， 形成了一个反馈回路， 通过激活MMPs而造成血脑屏障的不断破坏。 此外， Caveolin-1 通过调节不同的信号通路， 抑制神经干细胞的增长及向神经元分化。 因此， 活性氮也很可能通过调节Caveolin-1及其他信号通路调控神经再生。 在这篇文章中， 我们对活性氮在血脑屏障及神经再生中的近期研究进展进行了综述。 我们认为， 活性氮可能在脑缺血再灌注中起双重作用， 既是细胞毒性分子， 亦可能是神经再生中的重要信号分子， 其作用与其在神经元、 内皮细胞及其微环境中产生的量有重要的关系。