L-Cysteine Provides Neuroprotection of Hypoxia-Ischemia Injury in Neonatal Mice via a PI3K/Akt-Dependent Mechanism

Abstract

Background: Previous work within our laboratory has revealed that hydrogen sulfide (H 2 S) can serve as neuroprotectant against brain damage caused by hypoxia-ischemia (HI) exposure in neonatal mice. After HI insult, activation of the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt) signaling pathway has been shown to be implicated in neurorestoration processes. The goal of the current study was to determine whether the neuroprotective effects of H 2 S were mediated by the PI3K/Akt signaling pathway. Methods: The mouse HI model was built at postnatal day 7 (P7), and the effects of L-Cysteine treatment on acute brain damage (72 h post-HI) and long-term neurological responses (28 days post-HI) were evaluated. Nissl staining and Transmission electron microscopy were used to evaluate the neuronal loss and apoptosis. Immunofluorescence imaging and dihydroethidium staining were utilized to determine glial cell activation and ROS content, respectively. Results: Quantitative results revealed that L-Cysteine treatment significantly prevented the acute effects of HI on apoptosis, glial cell activation and oxidative injury as well as the longterm effects upon memory impairment in neonatal mice. This protective effect of L-Cysteine was found to be associated with the phosphorylation of Akt and phosphatase and a tensin homolog deletion on chromosome 10 (PTEN). Following treatment with the PI3K inhibitor, LY294002, the neuroprotective effects of L-Cysteine were attenuated. Conclusion: PTEN/PI3K/Akt signaling was involved in mediating the neuroprotective effects of exogenous H 2 S against HI exposure in neonatal mice.

Hydrogen Sulfide Attenuates Lymphedema Via the Induction of Lymphangiogenesis Through a PI3K/Akt‐Dependent Mechanism

“…H 2 S modulates the PI3K/Akt pathway in multiple cells. 34 , 35 , 36 , 37 For instance, H 2 S exerts cardioprotection against ischemia–reperfusion injury and against pressure‐overload heart failure models via Akt phosphorylation. 38 , 39 H 2 S has also been reported to modulate PI3K‐Akt signaling in vascular smooth muscle cells against high glucose‐induced apoptosis.…”

Hydrogen sulfide donor AP123 restores endothelial nitric oxide-dependent vascular function in hyperglycemia via a CREB-dependent pathway

“…This hypothesis of mechanism well fit with previous evidence showing that activation of PI3K/eNOS signaling by H 2 S directly modulated NO levels in BAEC [ 76 ] and exerts a protective effect in HG-induced injury in HUVEC cells [ 77 ]. Furthermore, the activation of this pathway has also been demonstrated to be beneficial in vivo, in a model of cardiac dysfunction associated with sepsis [ 78 ] as well as in neuronal hypoxia-ischemia injury or angiogenesis models [ 79 , 80 ].…”

Neurovascular protection of alisol A on cerebral ischemia mice through activating the AKT/GSK3β pathway

“…Both Cho and MI levels increased after ischemia, indicating overactivation of glia after ischemia. Interestingly, AKT is a crucial regulator of cell energy metabolism, including cholinergic function, neurochemical differentiation, neuroprotection and inhibition of gliosis [ 30 ]. It was confirmed that activation of AKT regulated the levels of MI, Cho and NAA [ 18 ].…”