Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H(2)S system: Role of oxidative stress and endoplasmic reticulum stress.
Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H(2)S system: Role of oxidative stress and endoplasmic reticulum stress.
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DOI：
10.1016/j.redox.2017.06.007
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发表时间：
2017-10
期刊：
影响因子：
11.4
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Liu S;Xin D;Wang L;Zhang T;Bai X;Li T;Xie Y;Xue H;Bo S;Liu D;Wang Z
新生儿缺氧缺血性损伤是新生儿死亡和神经功能障碍的主要原因。H2S对缺氧引起的神经元损伤和凋亡有保护作用。L-半胱氨酸由脑中的胱硫醚-β-合酶（CBS）催化，并随后产生内源性H2S。本研究旨在探讨L-Cysteine是否能通过释放内源性H2S减轻新生小鼠HI脑损伤后的急性脑损伤并改善其神经行为功能。L-半胱氨酸治疗显着减弱脑水肿，减少梗死体积和神经元细胞死亡，如所示的Bax/Bcl-2的比例下降，抑制caspase-3的激活，并减少Akt和ERK的磷酸化在HI后72小时。此外，L-半胱氨酸显著上调NF-E2相关因子2和血红素加氧酶-1的表达。L-半胱氨酸也降低内质网（ER）应激相关的促凋亡蛋白的表达。此外，L-半胱氨酸通过保护同侧脑组织的损失和改善神经行为结果而具有长期作用。重要的是，用CBS抑制剂预处理显著减弱了L-半胱氨酸对HI损伤的神经保护作用。因此，L-半胱氨酸通过CBS/H2S途径对新生儿HI诱导的损伤发挥神经保护作用，部分由抗凋亡作用和减少的氧化应激和ER应激介导。因此，L-半胱氨酸可能是HI的有希望的治疗。HI损伤后24 h给予L-半胱氨酸具有神经保护作用。L-半胱氨酸管理衰减HI诱导的氧化应激和ER应激。在HI损伤后14天和28天，给予L-半胱氨酸对改善神经行为功能具有长期作用。CBS抑制剂预处理显著减弱了L-半胱氨酸对新生小鼠HI的神经保护作用。
Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72 h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI. L-Cysteine administration at 24 h after HI insult has neuroprotective effect. L-Cysteine administration attenuated HI-induced oxidative stress and ER stress. L-Cysteine administration had long-term effects in improving neurobehavioral function at 14 and 28 days after HI insult. Pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI in neonatal mice.
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