title: Galanin Protects from Caspase-8/12-initiated Neuronal Apoptosis in the Ischemic Mouse Brain via GalR1.
abstract: 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 andin vitrocell 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 ofGALmRNA during 24-48 h R (p<0.001), and GAL receptorsGalR1-2(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.
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Mei
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Shuiqiao
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Xiao-Xiao
authors.initials: XX
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Junfa
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
authors.forename: Zhi-Qing David
authors.initials: ZD
authors.lastname: Xu
keywords: Apoptosis; Neuroprotection; Neurotransmitters; Receptors; Stroke