Psychosine blocks quisqualate-induced glutamate excitotoxicity in hippocampal CA sector neurons.
Quisqualate is a potent specific agonist for Group 1 metabotropic glutamate receptors (mGluR's), that activate G protein-coupled phospholipase C (PLC) in a molecular signal-transduction mechanism that raises cytoplasmic Ca2+ and, when excessive, damages hippocampal neurons. Psychosine (beta-galactosylsphingosine), a cationic lysosphingolipid occurring naturally in nervous tissues, dose-dependently inhibited PLC activation induced by metabotropic alpha 1-adrenergic receptor signaling in cultured rat brain astrocytes in vitro. In the present study, we have tested neuroprotective efficacy of psychosine in vivo, in a rat model of glutamate excitotoxicity induced by intracerebroventricular (i.c.v.) administration of quisqualate. A sublethal i.c.v. dose of quisqualate caused episodes of prolonged akinesia and convulsions, and major damage to pyramidal neurons of the hippocampal CA1 and CA3 sector, but not to granule cell neurons of the dentate gyrus. Prior infusion of psychosine greatly attenuated quisqualate-induced behaviors, and fully prevented destruction by quisqualate of vulnerable hippocampal neurons. Psychosine may prove useful in prophylaxis of neurodegenerative disorders that arise from intensive hippocampal Group 1 mGluR stimulation.
Hodgson
D M
DM
Brain Research Institute, School of Medicine, University of California, Los Angeles 90095, USA.
Taylor
A N
AN
Zhang
Z
Z
Rosenberg
A
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011609:Psychosine / Q000494:pharmacology*; D016318:Quisqualic Acid / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D018690:Excitatory Amino Acid Agonists; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D011609:Psychosine; D016318:Quisqualic Acid