title: Pro-apoptotic function of GABA-related transcripts following stroke.
abstract: Following cerebral injuries such as stroke, a structural and functional reorganization of the impaired tissue occurs, which is often accompanied by a re-expression of developmental genes. During brain development, embryonic splice variants of the GABA-synthesizing GAD67 gene (collectively termed EGAD) participate in cell proliferation, migration, and neuronal differentiation. We thus hypothesized an involvement of EGAD in post-ischemic plasticity. EGAD transcripts were up-regulated at early reperfusion times in the injured area following transient middle cerebral artery occlusion (with a peak expression of 4.5-fold at 6h in C57BL/6 mice). Cell-specific analysis by a combination of radioactive in situ hybridization and immunolabeling revealed EGAD up-regulation in TUNEL-positive neurons. This unexpected cell death-associated expression of EGAD was confirmed in cell culture models of ischemia (combined oxygen-glucose deprivation) and apoptosis (staurosporine). Staurosporine-mediated cell death led to cleaved Caspase-3 activation, a key regulator of apoptosis following stroke. Blocking of staurosporine-associated EGAD expression via antisense RNA treatment reduced cleaved Caspase-3 activation by ~30%. In addition to the involvement of EGAD in proliferative processes during brain development, we found here that EGAD participates in cell death under pathophysiological conditions in the adult brain. Re-expression of EGAD in neurons following stroke may play a role in aberrant cell cycle activation, consequently being pro-apoptotic. Our observation of a new GABA related pro-apoptotic mechanism and its successful modification might be of significant clinical relevance.
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jaenisch
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Popp
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Guenther
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schnabel
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany; CSCC, Center for Sepsis Control and Care, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Otto W
authors.initials: OW
authors.lastname: Witte
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany. Electronic address: christiane.frahm@med.uni-jena.de.
authors.forename: Christiane
authors.initials: C
authors.lastname: Frahm
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D002545:Brain Ischemia / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D020033:Protein Isoforms; D017208:Rats, Wistar; D019311:Staurosporine / Q000633:toxicity; D020521:Stroke / Q000503:physiopathology*
chemical_list: D020033:Protein Isoforms; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D019311:Staurosporine; D005947:Glucose
keywords: Apoptosis; EGAD; GABA; MCAO; Staurosporine