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

doi:10.1016/j.expneurol.2019.112978

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

Exp Neurol. 2019 Oct:320:112978. doi: 10.1016/j.expneurol.2019.112978. Epub 2019 Jun 15.

Authors

Affiliations

¹ Department of Neurology, Medical School, RWTH Aachen University, Aachen, Germany. Electronic address: phabib@ukaachen.de.
² Department of Neurology, Medical School, RWTH Aachen University, Aachen, Germany.
³ Institute of Neuroanatomy, Medical School, RWTH Aachen University, Aachen, Germany.
⁴ Institute of Biochemistry and Molecular Immunology, Medical School, RWTH Aachen University, Aachen, Germany.
⁵ Department of Neurology, Medical School, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany.

PMID: 31211943
DOI: 10.1016/j.expneurol.2019.112978

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.

Keywords: Erythropoietin; MCAo; OGD, GRINA, FAIM2; Stroke.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Ischemia* / metabolism
Epoetin Alfa* / pharmacology
Infarction, Middle Cerebral Artery / metabolism
Infarction, Middle Cerebral Artery / pathology
Male
Membrane Proteins* / metabolism
Mice
Mice, Knockout
Nerve Tissue Proteins* / metabolism
Neuroprotective Agents / pharmacology
Reperfusion Injury* / metabolism
Reperfusion Injury* / pathology

Substances

Epoetin Alfa
Grina protein, mouse
lifeguard protein, mouse
Membrane Proteins
Nerve Tissue Proteins
Neuroprotective Agents