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.
Parker
Mark A
MA
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Bazan
Haydee E P
HE
Marcheselli
Victor
V
Rodriguez de Turco
Elena B
EB
Bazan
Nicolas G
NG
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