Lysosphingomyelin prevents behavioral aberrations and hippocampal neuron loss induced by the metabotropic glutamate receptor agonist quisqualate.
1. Excessive excitation of brain neurons by the excitatory neurotransmitter, glutamate, induces a cascade of events leading to increased intracellular Ca++, neuronal degeneration and death. 2. Recent in vitro research has demonstrated that a natural cationic amphiphile in the brain, lysosphingomyelin, may be able to prevent neuronal degeneration by repressing phosphosinositidase-C overactivation induced by excessive excitation of the metabotropic glutamate receptor. 3. This research tested the latter finding in vivo in a rat model of glutamate excitotoxicity. Intracerebroventricular (i.c.v.) administration of the Group 1 metabotropic glutamate receptor (mGluR) agonist, quisqualate, produced seizures, akinesia, destruction of hippocampal pyramidal cell dendritic microtubule-associated protein-2, and major loss of hippocampal CA sector neurons. 4. Prophylactic i.c.v. infusion of lysosphingomyelin powerfully attenuates these quisqualate-induced behaviors and prevents neuronal degeneration. 5. Lysosphingomyelin may be of clinical use in allaying progressive Group 1 mGluR-induced hippocampal cognitive and motor disorders including Alzheimer's disease, brain seizure, and stroke.
Hodgson
D M
DM
Dept. of Neurobiology, School of Medicine, University of California, Los Angeles, USA.
Taylor
A N
AN
Zhang
Z
Z
Rosenberg
A
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004409:Dyskinesia, Drug-Induced / Q000523:psychology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D020547:Lateral Ventricles; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016318:Quisqualic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D008869:Microtubule-Associated Proteins; D018094:Receptors, Metabotropic Glutamate; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D016318:Quisqualic Acid; D013110:Sphingosine