Platelet-activating factor induces permeability transition and cytochrome c release in isolated brain mitochondria.
Platelet-activating factor (PAF), a potent bioactive phospholipid implicated in neuronal excitotoxic death, was assessed as a mediator of brain mitochondrial dysfunction. Carbamyl PAF, a non-hydrolyzable PAF analog, added to neurons in culture resulted in decreased mitochondrial membrane potential (DeltaPsi(M)) as measured by the DeltaPsi(M)-sensitive fluorophore 5,5', 6,6'-tetrachloro-1, 1', 3,3'-tetraethylethylbenzimidazolo-carbocyanide iodide (JC-1). To investigate whether PAF has a direct effect on the mitochondria, the mediator was added to rat brain mitochondria preparations and an increase in the permeability of the mitochondrial membrane, termed permeability transition (PT), and cytochrome c release were measured. We report that PAF causes both dose-dependent PT and cytochrome c release from isolated mitochondria. Furthermore, the selective PAF antagonist tetrahydro-4,7,8,10 methyl-1 (chloro-2 phenyl)-6 (methoxy-4 phenyl-carbamoyl)-9 pyrido [4',3'-4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4 (BN50730), which has affinity for intracellular binding sites, and the peripheral benzodiazepine receptor ligands 7-chloro-5- [4'-chlorophenyl]-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864) and 1-(-2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), inhibit PAF induction of PT and cytochrome c release. These results suggest that PAF excitotoxicity involves, at least in part, alterations of the mitochondrial membrane.
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Mark A
MA
Parker
Haydee E P
HE
Bazan
Victor
V
Marcheselli
Elena B
EB
Rodriguez de Turco
Nicolas G
NG
Bazan
D000818:Animals; D003574:Cytochrome c Group / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010972:Platelet Activating Factor / Q000378:metabolism / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D003574:Cytochrome c Group; D010972:Platelet Activating Factor