Open AccessGalanin Protects from Caspase-8/12-initiated Neuronal Apoptosis in the Ischemic Mouse Brain via GalR1
Author(s) -
Yun Li,
Mei Zhu,
Shuiqiao Liu,
Tong Wang,
Hui Li,
Xiaoxiao Li,
Song Han,
Yutao Yang,
Junfa Li,
ZhiQing David Xu
Publication year - 2017
Publication title -
aging and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.808
H-Index - 54
ISSN - 2152-5250
DOI - 10.14336/ad.2016.0806
Subject(s) - neuroprotection , galanin , gene knockdown , receptor , ischemia , apoptosis , pharmacology , medicine , agonist , stroke (engine) , knockout mouse , endocrinology , chemistry , neuropeptide , biochemistry , mechanical engineering , engineering
Galanin (GAL) plays key role in many pathophysiological processes, but its role in ischemic stroke remains unclear. Here, the models of 1 h middle cerebral artery occlusion (MCAO)/1-7 d reperfusion (R)-induced ischemic stroke and in vitro cell ischemia of 1 h oxygen-glucose deprivation (OGD)/24 h reoxygenation in primary cultured cortical neurons were used to explore GAL's effects and its underlying mechanisms. The results showed significant increases of GAL protein levels in the peri-infarct region (P) and infarct core (I) within 48 h R of MCAO mice ( p <0.001). The RT-qPCR results also demonstrated significant increases of GAL mRNA during 24-48 h R ( p <0.001), and GAL receptors GalR1-2 (but not 3) mRNA levels in the P region at 24 h R of MCAO mice ( p <0.001). Furthermore, the significant decrease of infarct volume ( p <0.05) and improved neurological outcome ( p <0.001-0.05) were observed in MCAO mice following 1 h pre- or 6 h post-treatment of GAL during 1-7 d reperfusion. GalR1 was confirmed as the receptor responsible for GAL-induced neuroprotection by using GalR2/3 agonist AR-M1896 and Lentivirus-based RNAi knockdown of GalR1. GAL treatment inhibited Caspase-3 activation through the upstream initiators Capsases-8/-12 (not Caspase-9) in both P region and OGD-treated cortical neurons. Meanwhile, GAL's neuroprotective effect was not observed in cortical neurons from conventional protein kinase C (cPKC) γ knockout mice. These results suggested that exogenous GAL protects the brain from ischemic injury by inhibiting Capsase-8/12-initiated apoptosis, possibly mediated by GalR1 via the cPKCγ signaling pathway.