Abstract
Hypoxia-inducible factor 1 can sufficiently control the progress of neurological symptoms after ischemic stroke owing to their actions associated with its downstream genes. In this study, we evaluated the role of HIF-1α in attenuating brain damage after endothelin-1 injection. Focal cerebral ischemia in mice were induced by endothelin-1 microinjection. Hypoxia-inducible factor 1 activator, dimethyloxalylglycine (DMOG), and HIF-1α inhibitor, acriflavine (ACF), were used to evaluate the hypoxia-inducible factor 1 activity during cerebral ischemia. The expression levels of HIF-1α, glial fibrillary acidic protein (GFAP), interleukin-10 (IL-10), inducible nitric oxide synthase (iNOS), phosphorylated I-kappa-B-alpha/total I-kappa-B-alpha (p-IκBα/IκBα) and nuclear factor kappa B (NF-kB) were assessed. Besides, mRNA levels of IL-10, tumor necrosis factor- alpha (TNF-α), and NF-kB were also analyzed. Results showed a noticeable increase in hypoxia-inducible factor 1 and IL-10 levels in the DMOG group with a decline in iNOS, TNF-α, and NF-kB levels, implying the anti-inflammatory role of hypoxia-inducible factor 1 activator following stroke. These findings were further corroborated by GFAP immunostaining that showed astrocytic activation to be inhibited 12 days post-ischemia, as well as histological and TEM analyses that demonstrated hypoxia-inducible factor 1 induction to alleviate neuronal soma damage and cell death. Based on our study, HIF-1α could be a potential therapeutic target for ischemic stroke.
Highlights
Cerebrovascular diseases, ischemic stroke, have been widely studied because of their severe outcomes [1]
The modulation of HIF-1α activity can occur by using prolyl-4-hydroxylase domain (PHD) inhibitors and drugs that interfere with heterodimer formation [29]
In ascertaining the contribution of HIF-1α to stroke recovery, we found that DMOG enhanced neuronal cell survival, and improved neuronal soma deficits that had been induced by stroke
Summary
Cerebrovascular diseases, ischemic stroke, have been widely studied because of their severe outcomes [1]. Induction of angiogenesis is an effective pathway towards increasing the oxygenation of hypoxic tissue In this context, hypoxia-inducible factor 1 (HIF-1α) can regulate the expression of numerous genes, and enhance the adaptability to minimal O2 environment [4]. A previous study confirmed microinjection of endothelin-1 [ET-1] as an effective method to induce acute focal ischemia where striatum and parietal cortex were damaged [21,22,23]. This peptide is convenient for creating focal strokes that repeatedly takes place in the human brain [24,25,26]. Histological and ultrastructure analyses of corresponding brain tissue after ischemia confirmed such pivotal role of HIF-1α activation
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