title: Inhibitory modulation of the mitochondrial permeability transition by minocycline.
abstract: 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.
authors.affiliation: Institute of Medical Neurobiology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gieseler
authors.forename: Adrian Tilman
authors.initials: AT
authors.lastname: Schultze
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kupsch
authors.forename: Mohammad Fahad
authors.initials: MF
authors.lastname: Haroon
authors.forename: Gerald
authors.initials: G
authors.lastname: Wolf
authors.forename: Detlef
authors.initials: D
authors.lastname: Siemen
authors.forename: Peter
authors.initials: P
authors.lastname: Kreutzmann
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D016166:Free Radical Scavengers; D012402:Rotenone; D045304:Cytochromes c; D008911:Minocycline; D002118:Calcium