A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures.
Lysophospholipids (LPLs) are important intermediates in the synthesis and degradation of membrane phospholipids. Here we show that certain LPLs, particularly lysophosphatidylcholine and lysophosphatidylinositol, prevent neuronal death both in an in vivo model of transient global ischemia and in an in vitro model of excitotoxicity using primary cultures of cerebellar granule cells exposed to high extracellular concentrations of glutamate (20-40 micromol/L). The intravenous injection of lysophosphatidylcholine or lysophosphatidylinositol at a concentration of 200 nmol/kg induced a survival of CA1 pyramidal neurons as high as approximately 95%, even when the treatment was started 30 minutes after 15-minute global ischemia. In contrast, lysophosphatidic acid induced no protection. This work also provides evidence that a pretreatment with lysophosphatidylcholine or lysophosphatidylinositol (200 nmol/kg) injected as long as 3 days before a severe 6-minute ischemia provided a potent tolerance against neurodegeneration. Neuroprotection was also observed in in vitro experiments with LPLs. Taken together, in vivo and in vitro data suggest a potential therapeutic use of LPLs as antiischemic compounds. The potential role of 2P-domain K+ channels as targets of LPLs in this potent neuroprotective effect is discussed.
Blondeau
Nicolas
N
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Valbonne, France.
Lauritzen
Inger
I
Widmann
Catherine
C
Lazdunski
Michel
M
Heurteaux
Catherine
C
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018698:Glutamic Acid / Q000633:toxicity*; D018840:HSP70 Heat-Shock Proteins / Q000302:isolation & purification; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control*; D007700:Kinetics; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010712:Phosphatidic Acids / Q000494:pharmacology; D016548:Prosencephalon; D051381:Rats; D017208:Rats, Wistar
D018840:HSP70 Heat-Shock Proteins; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010712:Phosphatidic Acids; C025449:lysophosphatidylinositol; C006065:We 201; D018698:Glutamic Acid