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

摘要

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.