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EPO Regulates Neuroprotective Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) Family Members GRINA and FAIM2 After Cerebral Ischemia-Reperfusion Injury

EPO Regulates Neuroprotective Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) Family Members GRINA and FAIM2 After Cerebral Ischemia-Reperfusion Injury

Pardes Habib, Ann-Sophie Stamm, Thomas Zeyen, Rozina Noristani, Alexander Slowik, Cordian Beyer, Thomas Wilhelm, Michael Huber, Daniel Komnig, Jörg B Schulz, Arno Reich

Exp Neurol. 2019 Oct;320:112978.

PMID: 31211943

Abstract:

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 (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.
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413264	Erythropoietin from mouse			Price

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