Baclofen is neuroprotective and prevents loss of calcium/calmodulin-dependent protein kinase II immunoreactivity in the ischemic gerbil hippocampus.
Excessive release of glutamate during transient cerebral ischemia initiates a cascade of events that leads to the delayed and selective death of neurons located in the hippocampus. Activity of calcium calmodulin kinase II (CaM kinase), a protein kinase critical to neuronal functioning, disappears following ischemia. The in vivo link between glutamate excitoxicity and alterations in CaM kinase activity has not been extensively studied. Baclofen, a selective gamma-aminobutyric acid (GABA)(B) receptor agonist, has been shown to inhibit glutamate release. The present study evaluated the neuroprotective efficacy of this compound and assessed early changes in hippocampal-dependent behaviors and CaM kinase immunoreactivity following transient cerebral ischemia. Baclofen (50 mg/kg) prevented both the loss of hippocampal CA1 pyramidal cells and the reduction in hippocampal CaM kinase immunoreactivity observed in control animals following ischemic insult. Cerebral ischemia produced a significant increase in working memory errors; however, baclofen failed to attenuate this memory deficit. Results confirm that baclofen is neuroprotective and support a link between glutamate excitotoxicity and reductions in CaM kinase immunoreactivity.
Babcock
Alex M
AM
Department of Psychology, Montana State University, Bozeman, Montana 59715, USA. upymb@montana.edu
Everingham
Andi
A
Paden
Charles M
CM
Kimura
Maki
M
D000818:Animals; D000906:Antibodies; D001418:Baclofen / Q000494:pharmacology*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis* / Q000276:immunology; D004591:Electrophoresis, Polyacrylamide Gel; D018755:GABA Agonists / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000201:enzymology*; D007150:Immunohistochemistry; D008570:Memory, Short-Term / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000378:metabolism
D000906:Antibodies; D018755:GABA Agonists; D018696:Neuroprotective Agents; D018080:Receptors, GABA-B; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D001418:Baclofen