Neuroprotective Roles of l-Cysteine in Attenuating Early Brain Injury and Improving Synaptic Density via the CBS/H(2)S Pathway Following Subarachnoid Hemorrhage in Rats.
Neuroprotective Roles of l-Cysteine in Attenuating Early Brain Injury and Improving Synaptic Density via the CBS/H(2)S Pathway Following Subarachnoid Hemorrhage in Rats.
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DOI：
10.3389/fneur.2017.00176
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发表时间：
2017
影响因子：
3.4
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Li T;Wang L;Hu Q;Liu S;Bai X;Xie Y;Zhang T;Bo S;Gao X;Wu S;Li G;Wang Z
L-半胱氨酸是中枢神经系统中胱硫氨酸-β-合成酶的半必需氨基酸和底物。我们之前曾报道，硫化氢供体NaHS显著减轻了大鼠蛛网膜下腔出血(SAH)后的脑损伤。然而，L-半胱氨酸的潜在治疗价值和支持这些有益作用的分子机制尚未确定。本研究旨在探讨L-半胱氨酸能否通过释放内源性H_2S减轻蛛网膜下腔出血后早期脑损伤，改善突触功能。雄性Wistar大鼠采用枕大池注射法建立蛛网膜下腔出血模型，蛛网膜下腔出血后30 脑室注射L-半胱氨酸。L-半胱氨酸处理可刺激前额叶皮质CBS活性和H_2S的产生。此外，L-半胱氨酸治疗可明显减轻蛛网膜下腔出血后48 脑组织中bax/bcl2的比值，抑制caspase3的激活，并能明显减轻前额叶皮质的脑水肿，改善神经行为功能，减轻神经细胞死亡。此外，L-半胱氨酸可通过调节突触蛋白，激活蛛网膜下腔出血后48 h的CREB-脑源性神经营养因子通路，增强突触密度。重要的是，L-半胱氨酸对蛛网膜下腔出血的所有有益作用都被CBS抑制剂氨基氧乙酸所消除。基于这些发现，L-半胱氨酸可能通过抑制细胞凋亡、上调CREB-BDNF的表达、促进突触结构，通过CBS/H_2S途径在SAH中发挥神经保护作用。
l-Cysteine is a semi-essential amino acid and substrate for cystathionine-β-synthase (CBS) in the central nervous system. We previously reported that NaHS, an H2S donor, significantly alleviated brain damage after subarachnoid hemorrhage (SAH) in rats. However, the potential therapeutic value of l-cysteine and the molecular mechanism supporting these beneficial effects have not been determined. This study was designed to investigate whether l-cysteine could attenuate early brain injury following SAH and improve synaptic function by releasing endogenous H2S. Male Wistar rats were subjected to SAH induced by cisterna magna blood injection, and l-cysteine was intracerebroventricularly administered 30 min after SAH induction. Treatment with l-cysteine stimulated CBS activity in the prefrontal cortex (PFC) and H2S production. Moreover, l-cysteine treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the PFC; these effects were associated with a decrease in the Bax/Bcl-2 ratio and the suppression of caspase-3 activation 48 h after SAH. Furthermore, l-cysteine treatment activated the CREB–brain-derived neurotrophic factor (BDNF) pathway and intensified synaptic density by regulating synapse proteins 48 h after SAH. Importantly, all the beneficial effects of l-cysteine in SAH were abrogated by amino-oxyacetic acid, a CBS inhibitor. Based on these findings, l-cysteine may play a neuroprotective role in SAH by inhibiting cell apoptosis, upregulating CREB–BDNF expression, and promoting synaptic structure via the CBS/H2S pathway.