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PMID: 18699862 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Ischemic insult to cerebellar Purkinje cells causes diminished GABAA receptor function and allopregnanolone neuroprotection is associated with GABAA receptor stabilization.

Journal of neurochemistry ·Vol. 107 ·No. 3 ·2008-11-00 ·Pages 668-78

Kelley MH, Taguchi N, Ardeshiri A, Kuroiwa M, Hurn PD, Traystman RJ, Herson PS

Abstract

Cerebellar Purkinje cells (PC) are particularly vulnerable to ischemic injury and excitotoxicity, although the molecular basis of this sensitivity remains unclear. We tested the hypothesis that ischemia causes rapid down-regulation of GABA(A) receptors in cerebellar PC, thereby increasing susceptibility to excitotoxicity. Oxygen-glucose deprivation (OGD) caused a decline in functional GABA(A) receptors, within the first hour of re-oxygenation. Decreased amplitude of miniature inhibitory post-synaptic potentials confirmed that OGD caused a significant decrease in functional synaptic GABA(A) receptors and quantitative Western blot analysis demonstrated the loss of GABA(A) receptor current was associated with a decline in total receptor protein. Interestingly, the potent neuroprotectant allopregnanolone (ALLO) prevented the decline in GABA(A) receptor current and protein. Consistent with our in vitro data, global ischemia in mice caused a significant decline in total cerebellar GABA(A) receptor protein and PC specific immunoreactivity. Moreover, ALLO provided strong protection of PC and prevented ischemia-induced decline in GABA(A) receptor protein. Our findings indicate that ischemia causes a rapid and sustained loss of GABA(A) receptors in PC, whereas ALLO prevents the decline in GABA(A) receptors and protects against ischemia-induced damage. Thus, interventions which prevent ischemia-induced decline in GABA(A) receptors may represent a novel neuroprotective strategy.

MeSH Terms
Animals Blotting, Western Brain Ischemia/metabolism Immunohistochemistry Inhibitory Postsynaptic Potentials/drug effects,physiology Mice Neuroprotective Agents/pharmacology Patch-Clamp Techniques Pregnanolone/pharmacology Purkinje Cells/drug effects,metabolism,pathology Rats Rats, Sprague-Dawley Receptors, GABA-A/drug effects,metabolism Reverse Transcriptase Polymerase Chain Reaction
Chemicals
Neuroprotective Agents Receptors, GABA-A Pregnanolone
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kelley Melissa H
Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon 97201, USA.
Taguchi Noriko
Ardeshiri Ardalan
Kuroiwa Masayuki
Hurn Patricia D
Traystman Richard J
Herson Paco S
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Article Info
Journal
Journal of neurochemistry
Abbr.
J Neurochem
ISSN
1471-4159
DOI
10.1111/j.1471-4159.2008.05617.x
Published
2008-11-00
Epub
2008-00-18
Pages
668-78
Language
English
Region
England
NLM ID
2985190R
PMCID
PMC2692389
Subset
IM
Grants
NINDS NIH HHS · R21 NS052591 · United States
NINDS NIH HHS · R01 NS058792 · United States
NINDS NIH HHS · T332NS007466-09 · United States
NINDS NIH HHS · T32 NS007466 · United States
NINDS NIH HHS · R21NS052591 · United States
NINDS NIH HHS · R01 NS058792-02 · United States
NINDS NIH HHS · R01NS058792 · United States
External Links
PubMed source DOI: 10.1111/j.1471-4159.2008.05617.x PMC Full Text View journal details
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