title: Promethazine protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.
abstract: Promethazine (PMZ) is an FDA-approved antihistaminergic drug that was identified as a potentially neuroprotective compound in the NINDS screening program. PMZ accumulates in brain mitochondria in vivo and inhibits Ca2+-induced mitochondrial permeability transition pore (PTP) in rat liver mitochondria in vitro. We hypothesized that PMZ may have a protective effect in a mitochondrial toxin model of Parkinson's disease (PD). Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) sustained a significant loss of dopaminergic neurons within the SNpc that was strongly attenuated by PMZ treatment. However, neither striatal MPP+ concentrations nor MPTP-induced inhibition of mitochondrial complex I were affected by PMZ treatment. In isolated mouse brain mitochondria, PMZ partially prevented and reversed MPP+-induced depolarization of membrane potential and inhibited the Ca2+-induced PTP in brain mitochondria. The sum of data indicates that PMZ is a strong neuroprotective agent capable of protecting dopaminergic neurons against MPTP toxicity in vivo.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, Room A-501, NY 10021, USA. cac2005@med.cornell.edu
authors.forename: Carine
authors.initials: C
authors.lastname: Cleren
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lorenzo
authors.forename: Junya
authors.initials: J
authors.lastname: Chen
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000187:drug effects / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011398:Promethazine / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D006634:Histamine H1 Antagonists; D018696:Neuroprotective Agents; D042967:Electron Transport Complex I; D011398:Promethazine; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium; D004298:Dopamine