Format

Send to

Choose Destination
See comment in PubMed Commons below
Neurobiol Dis. 2014 Oct;70:237-44. doi: 10.1016/j.nbd.2014.06.015. Epub 2014 Jun 28.

Pro-apoptotic function of GABA-related transcripts following stroke.

Author information

1
Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany.
2
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.
3
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.

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.

KEYWORDS:

Apoptosis; EGAD; GABA; MCAO; Staurosporine

PMID:
24983209
DOI:
10.1016/j.nbd.2014.06.015
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center