Abstract
Stroke remains the leading cause of death and disability worldwide, which destroys the quality of patients’ lives and thus is becoming a heavy burden to the society. However, the current therapeutic approaches are far from satisfaction. The objective of this study is to elucidate the impact of nerve growth factor (NGF) on the brain damage induced by cerebral ischemia and its potential molecular mechanism. Middle cerebral artery occlusion (MCAO) rats were used as animal models and neurological functions were evaluated by modified Neurological Severity Score (NSS). Brain cell apoptosis was analyzed by TUNEL-positive staining while brain infarct size was determined according to 2% 2,3,5-triphenyltetrazolium chloride (TCC) staining volume. Rats receiving NGF demonstrated significantly alleviated brain damage, reflected by a substantial improvement in the neurobehavioral outcome, a decrease in brain cell apoptosis and shrinkage of brain infarct volume. Further analysis revealed a markedly elevated circulating vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) levels as well as a significant downregulation of SA10012 expression in NGF treated group compared with the untreated group. Strikingly, the protective effect of NGF on cerebral ischemic injury was abolished in rats treated with both NGF and PI3K inhibitors, indicating that phosphoinositide-3-kinase (PI3K) signaling is essential for NGF function. In conclusion, NGF treatment might be a potential therapeutic approach against cerebral infarction by downregulating SA10012 expression and upregulating VEGF, SDF-1 in a PI3K signaling dependent manner.
Highlights
Despite the advances achieved in recent years, cerebral infarction still has high disability and mortality rates, which continues to be a severe threat to the human health (Bustamante et al, 2016)
We found that nerve growth factor (NGF) treatment limited the cerebral injury by upregulating the expression of the angiogenesis mediators, such as vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1)
According to the neurological function score measured at day 3 day post-surgery, rats receiving NGF treatment displayed significantly improvement in recovery compared to the untreated Middle cerebral artery occlusion (MCAO) rats (p < 0.05)
Summary
Despite the advances achieved in recent years, cerebral infarction still has high disability and mortality rates, which continues to be a severe threat to the human health (Bustamante et al, 2016). Nerve growth factor (NGF), produced by both neuron and microglia, is a neurotrophin that plays a pivotal role in the differentiation, maturation, and survival of neurons during development (Sofroniew et al, 2001). Deprivation of NGF still impacts the structural and functional plasticity of neurons in both peripheral and NGF induces angiogenesis (Greenberg and Jin, 2005) and prevents endothelial cell apoptosis in a ischemic wound. The impact of NGF in the reparative neovascularization of the cerebral ischemic injury remains unexplored. We found that NGF treatment limited the cerebral injury by upregulating the expression of the angiogenesis mediators, such as vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1). Inhibition of PI3K signaling almost completely abolished the protective effect of NGF against ischemic brain injury, which suggested that the NGF might function through PI3K pathway
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