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Platelet‐activating factor induces permeability transition and cytochrome c release in isolated brain mitochondria
Author(s) -
Parker Mark A.,
Bazan Haydee E. P.,
Marcheselli Victor,
Rodriguez de Turco Elena B.,
Bazan Nicolas G.
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10235
Subject(s) - platelet activating factor , mitochondrial permeability transition pore , mitochondrion , cytochrome c , chemistry , excitotoxicity , inner mitochondrial membrane , phospholipid , biochemistry , biology , microbiology and biotechnology , receptor , biophysics , apoptosis , programmed cell death , membrane , endocrinology , glutamate receptor
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 (ΔΨ M ) as measured by the ΔΨ 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. © 2002 Wiley‐Liss, Inc.