| First Author | Habib P | Year | 2019 |
| Journal | Exp Neurol | Volume | 320 |
| Pages | 112978 | PubMed ID | 31211943 |
| Mgi Jnum | J:282720 | Mgi Id | MGI:6381826 |
| Doi | 10.1016/j.expneurol.2019.112978 | Citation | Habib P, et al. (2019) EPO regulates neuroprotective Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family members GRINA and FAIM2 after cerebral ischemia-reperfusion injury. Exp Neurol 320:112978 |
| abstractText | BACKGROUND AND PURPOSE: Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family members exert inhibitory activities in apoptosis and necroptosis. FAIM2 (TMBIM-2) is neuroprotective against murine focal ischemia and is regulated by erythropoietin (EPO). Similar to FAIM2, GRINA (TMBIM-3) is predominantly expressed in the brain. The role of GRINA in transient brain ischemia, its potential synergistic effects with FAIM2 and its regulation by EPO treatment were assessed. METHODS: We performed transient (30min) middle cerebral artery occlusion (tMCAo) followed by 72h of reperfusion in GRINA-deficient (GRINA(-/-)), FAIM2-deficient (FAIM2(-/-)), double-deficient (GRINA(-/-)FAIM2(-/-)) and wildtype littermates (WT) mice. We administered EPO or saline 0, 24 and 48h after tMCAo. We subjected primary murine cortical neurons (pMCN) of all mouse strains to oxygen-glucose deprivation (OGD) after GRINA and/or FAIM2 gene transfection. RESULTS: Compared to wildtype controls GRINA deficiency led to a similar increase in infarct volumes as FAIM2 deficiency (p<.01). We observed the highest neurological deficits and largest infarct sizes in double-deficient mice. EPO administration upregulated GRINA and FAIM2 mRNA levels in wildtype littermates. EPO decreased infarct sizes and abrogated neurological impairments in wildtype controls. GRINA and/or FAIM2 deficient mice showed increased expression levels of cleaved-caspase 3 and of pro-apoptotic BAX mRNA. Further, caspase 8 was upregulated in FAIM2(-/-) and caspase 9 in GRINA(-/-) mice. Overexpression of GRINA and FAIM2 in wildtype and in double deficient pMCN decreased cell death rate after OGD. CONCLUSIONS: GRINA and FAIM2 are highly expressed in the brain and convey EPO-mediated neuroprotection after ischemic stroke involving different caspases. |
