Effect of 1-methyl-4-phenylpyridinium (MPP+) on mitochondrial membrane potential in cerebellar neurons: interaction with the NMDA receptor.
The effect of MPP+, a dopaminergic neurotoxin, in mitochondrial membrane potential was investigated in dissociated cerebellar granule cells using rhodamine 123 and flow cytometry. MPP+ (1 mM) decreased the mitochondrial membrane potential by 30%. Antagonists of the NMDA receptor complex, such as MK-801 (IC50 value of 20.92 +/- 0.02 nM), 5,7-dichlorokynurenic acid (IC50 value of 6.46 +/- 1.06 microM) and D-AP5 (IC50 value of 8.29 +/- 0.63 microM), inhibited the action of MPP+. Neither NBQX, nor riluzole, nor desipramine modified the action of MPP+. Dibucaine restored the basal values of mitochondrial membrane potential altered by MPP+. Since, in the presence of NMDA, MPP+ antagonized the effect of this total agonist, it can be concluded that, in this preparation, MPP+ interacts with the NMDA receptor complex as a partial agonist. This interaction could be the result of an allosteric modulation of the NMDA receptor complex by MPP+. The decrease of mitochondrial membrane potential induced by MPP+ is antagonized by dibucaine, suggesting that this effect is mediated by an activation of phospholipase A2.
Camins
A
A
Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Spain.
Sureda
F X
FX
Gabriel
C
C
Pallàs
M
M
Escubedo
E
E
Camarasa
J
J
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology*; D005434:Flow Cytometry; D007425:Intracellular Membranes / Q000187:drug effects; D016015:Logistic Models; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D015259:Dopamine Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D015655:1-Methyl-4-phenylpyridinium