Inhibitory modulation of the mitochondrial permeability transition by minocycline.
The semi-synthetic tetracycline derivative minocycline exerts neuroprotective properties in various animal models of neurodegenerative disorders. Although anti-inflammatory and anti-apoptotic effects are reported to contribute to the neuroprotective action, the exact molecular mechanisms underlying the beneficial properties of minocycline remain to be clarified. We analyzed the effects of minocycline in a cell culture model of neuronal damage and in single-channel measurements on isolated mitoplasts. Treatment of neuron-enriched cortical cultures with rotenone, a high affinity inhibitor of the mitochondrial complex I, resulted in a deregulation of the intracellular Ca2+-dynamics, as recorded by live cell imaging. Minocycline (100 microM) and cyclosporin A (2 microM), a known inhibitor of the mitochondrial permeability transition pore, decreased the rotenone-induced Ca2+-deregulation by 60.9% and 37.6%, respectively. Investigations of the mitochondrial permeability transition pore by patch-clamp techniques revealed for the first time a dose-dependent reduction of the open probability by minocycline (IC(50)=190 nM). Additionally, we provide evidence for the high antioxidant potential of MC in our model. In conclusion, the present data substantiate the beneficial properties of minocycline as promising neuroprotectant by its inhibitory activity on the mitochondrial permeability transition pore.
Gieseler
Anne
A
Institute of Medical Neurobiology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany.
Schultze
Adrian Tilman
AT
Kupsch
Kathleen
K
Haroon
Mohammad Fahad
MF
Wolf
Gerald
G
Siemen
Detlef
D
Kreutzmann
Peter
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D017136:Ion Transport; D008911:Minocycline / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D016166:Free Radical Scavengers; D012402:Rotenone; D045304:Cytochromes c; D008911:Minocycline; D002118:Calcium