The neuroprotective effects of Insulin-Like Growth Factor 1 via the Hippo/YAP signaling pathway are mediated by the PI3K/AKT cascade following cerebral ischemia/reperfusion injury.

Abstract

Insulin-like growth factor 1 (IGF-1) has neuroprotective actions, including vasodilatory, anti-inflammatory, and antithrombotic effects, following ischemic stroke. However, the molecular mechanisms underlying the neuroprotective effects of IGF-1 following ischemic stroke remain unknown. Therefore, in the present study, we investigated whether IGF-1 exerted its neuroprotective effects by regulating the Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT cascade, following ischemic stroke. In the in vitro study, we exposed cultured PC12 and SH-5YSY cells, and cortical primary neurons, to oxygen-glucose deprivation. Cell viability was measured using CCK-8 assay. In the in vivo study, Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neurological function was assessed using a modified neurologic scoring system and the modified neurological severity score (mNSS) test, brain edema was detected by brain water content measurement, infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis were evaluated by TUNEL/NeuN double staining, HE and Nissl staining, and immunohistochemistry staining for NeuN. Finally, western blot analysis was used to measure the level of IGF-1 in vivo and levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and reduced neurological deficits, brain water content, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were blocked by an inhibitor of the PI3K/AKT cascade, LY294002. LY294002 treatment not only downregulated PI3K and p-AKT, but YAP/TAZ as well, leading to aggravation of neurological dysfunction and worsening of brain damage. Our findings indicate that the neuroprotective effects of IGF-1 are, at least in part mediated by upregulation of YAP/TAZ via activation of the PI3K/AKT cascade following cerebral ischemic stroke.

• Authors: Pian Gong, Yichun Zou, Wei Zhang, Qi Tian, Shoumeng Han, Zhou Xu, Qianxue Chen, Xin Wang, Mingchang Li
• Journal: Brain research bulletin (Brain Res Bull) Vol. 177 Pg. 373-387 (12 2021) ISSN: 1873-2747 [Electronic] United States
• PMID: 34717965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Neuroprotective Agents
• YAP-Signaling Proteins
• Yap1 protein, rat
• Insulin-Like Growth Factor I
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Brain Ischemia (drug therapy, metabolism)
• Hippo Signaling Pathway
• Infarction, Middle Cerebral Artery (drug therapy, metabolism)
• Insulin-Like Growth Factor I (pharmacology)
• Neuroprotective Agents (pharmacology)
• PC12 Cells
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, metabolism)
• YAP-Signaling Proteins (metabolism)