Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): studies of cybrid cells bearing 11,778 mutation.
Leber's hereditary optic neuropathy (LHON) is a retinal neurodegenerative disorder caused by mitochondrial DNA point mutations. Complex I of the respiratory chain affected by the mutation results in a decrease in ATP and an increase of reactive oxygen species production. Evaluating the efficacy of minocycline in LHON, the drug increased the survival of cybrid cells in contrast to the parental cells after thapsigargin-induced calcium overload. Similar protection was observed by treatment with cyclosporine A, a blocker of the mitochondrial permeability transition pore (mPTP). Ratiometric Ca(2+) imaging reveals that acetylcholine/thapsigargin triggered elevation of the cytosolic calcium concentration is alleviated by minocycline and cyclosporine A. The mitochondrial membrane potential of LHON cybrids was significantly conserved and the active-caspase-3/procaspase-3 ratio was decreased in both treatments. Our observations show that minocycline inhibits permeability transition induced by thapsigargin in addition to its antioxidant effects. In relation with its high safety profile, these results would suggest minocycline as a promising neuroprotective agent in LHON.
Haroon
Mohammad Fahad
MF
Institute of Medical Neurobiology, Otto-von-Guericke University of Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany. Fahad.Haroon@medizin.uni-magdeburg.de
Fatima
Ambrin
A
Schöler
Susanne
S
Gieseler
Anne
A
Horn
Thomas F W
TF
Kirches
Elmar
E
Wolf
Gerald
G
Kreutzmann
Peter
P
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors