Lack of evidence of direct mitochondrial involvement in the neuroprotective effect of minocycline.
Minocycline has been reported to exert neuroprotection through inhibition of inflammatory processes and of mitochondrial cell death pathway. To further characterize the neuroprotective effect of minocycline, we determined its efficacy in different neuronal damage paradigms involving inflammation or mitochondrial dysfunction. In transient global ischaemia in gerbils, minocycline reduced hippocampal neuronal damage measured by peripheral type benzodiazepine binding sites density, a marker of microglial activation. The antiinflammatory properties of minocycline were confirmed on the model of carrageenan-induced paw oedema in rats. The use of two experimental animal models involving administration of mitochondrial toxins inhibiting a different complex of the mitochondrial respiratory chain permitted the exploration of the mitochondrial impact of minocycline. Although minocycline exhibited a marked efficacy in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP; complex I inhibitor)-induced neurotoxicity in mice, it was ineffective in malonate (complex II inhibitor)-induced striatal lesion in rats. In vitro investigations on energized mitochondria isolated from rat liver showed that minocycline (1 microM) did not inhibit the swelling induced by MPP+(1-methyl-4-phenylpyridinium). Moreover, higher concentrations of minocycline induced swelling. From these experiments, the neuroprotective activity of minocycline appears more related to its antiinflammatory activity than to a direct beneficial action on mitochondria.
Cornet
Sylvie
S
IPSEN: Institut Henri Beaufour, 5 avenue du Canada, 91966 Les Ulis, France.
Spinnewyn
Brigitte
B
Delaflotte
Sylvie
S
Charnet
Christelle
C
Roubert
Véronique
V
Favre
Christine
C
Hider
Hamida
H
Chabrier
P Etienne
PE
Auguet
Michel
M
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control; D002351:Carrageenan; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005849:Gerbillinae; D006614:Hindlimb; D007546:Isoquinolines / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D008933:Mitochondrial Swelling / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium
D007546:Isoquinolines; D008314:Malonates; D018696:Neuroprotective Agents; D014316:Tritium; D002351:Carrageenan; C030290:malonic acid; D008911:Minocycline; D004298:Dopamine; C037850:PK 11195