EPO regulates neuroprotective Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family members GRINA and FAIM2 after cerebral ischemia-reperfusion injury

• Published in: Experimental neurology Vol. 320; p. 112978
• Main Authors: Habib, Pardes, Stamm, Ann-Sophie, Zeyen, Thomas, Noristani, Rozina, Slowik, Alexander, Beyer, Cordian, Wilhelm, Thomas, Huber, Michael, Komnig, Daniel, Schulz, Jörg B., Reich, Arno
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Animals; Brain Ischemia - metabolism; Epoetin Alfa - pharmacology; Erythropoietin; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Male; MCAo; Membrane Proteins - metabolism; Mice; Mice, Knockout; Nerve Tissue Proteins - metabolism; Neuroprotective Agents - pharmacology; OGD, GRINA, FAIM2; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Stroke; MCAo; Stroke; Erythropoietin; OGD, GRINA, FAIM2
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2019.112978

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. We performed transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 72 h 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 48 h 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. 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. GRINA and FAIM2 are highly expressed in the brain and convey EPO-mediated neuroprotection after ischemic stroke involving different caspases. [Display omitted] •TMBIM family members FAIM2 (TMBIM2) and GRINA (TMBIM3) are highly expressed in the murine brain.•FAIM2 and GRINA seem to have synergistic or partly compensatory effects after stroke.•FAIM2 seems to be involved in the extrinsic (via caspase 8) and GRINA in the intrinsic (via caspase 9) apoptotic pathway.•EPO decreased infarct sizes, abrogated neurological deficits and up-regulated FAIM2 and GRINA mRNA after ischemic stroke.•TMBIM family members FAIM2 and GRINA are involved in EPO-mediated neuroprotection after stroke.