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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
1-Methyl-4-phenylpyridinium / metabolism
-
Animals
-
Calcium / metabolism
-
Calcium / pharmacology
-
Calcium Signaling / drug effects
-
Calcium Signaling / physiology
-
Disease Models, Animal
-
Dopamine / metabolism*
-
Electron Transport Complex I / drug effects
-
Electron Transport Complex I / physiology
-
Histamine H1 Antagonists / pharmacology
-
Male
-
Membrane Potentials / drug effects
-
Membrane Potentials / physiology
-
Mice
-
Mitochondria / drug effects
-
Mitochondria / metabolism
-
Mitochondrial Membranes / drug effects
-
Mitochondrial Membranes / metabolism
-
Nerve Degeneration / chemically induced
-
Nerve Degeneration / drug therapy
-
Nerve Degeneration / metabolism
-
Neurons / drug effects*
-
Neurons / metabolism
-
Neurons / pathology
-
Neuroprotective Agents / pharmacology
-
Parkinsonian Disorders / drug therapy*
-
Parkinsonian Disorders / metabolism
-
Parkinsonian Disorders / physiopathology
-
Promethazine / pharmacology*
-
Substantia Nigra / drug effects*
-
Substantia Nigra / metabolism
-
Substantia Nigra / physiopathology
Substances
-
Histamine H1 Antagonists
-
Neuroprotective Agents
-
Electron Transport Complex I
-
Promethazine
-
1-Methyl-4-phenylpyridinium
-
Calcium
-
Dopamine