Parkinson's disease (PD) is a neurodegenerative
movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra and depletion of the
neurotransmitter dopamine in the striatum. Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. Mechanistic studies using animal systems such as the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) rodent PD model have revealed the involvement of the brain's immune cells and
free radical-generating processes. We recently reported that
dextromethorphan (DM), a widely used anti-tussive agent, attenuated
endotoxin-induced dopaminergic neurodegeneration in vitro. In the current study, we investigated the potential
neuroprotective effect of DM and the underlying mechanism of action in the
MPTP rodent PD model. Mice (C57BL/6J) that received daily
MPTP injections (15 mg free base/kg
body weight, s.c.) for 6 consecutive days exhibited significant degeneration of the nigrostriatal dopaminergic pathway. However, the
MPTP-induced loss of nigral dopaminergic neurons was significantly attenuated in those mice receiving DM (10 mg/kg
body weight, s.c.). In mesencephalic neuron-glia cultures, DM significantly reduced the
MPTP-induced production of both extracellular
superoxide free radicals and intracellular
reactive oxygen species (ROS). Because
NADPH oxidase is the primary source of extracellular
superoxide and intracellular ROS, we investigated the involvement of
NADPH oxidase in the
neuroprotective effect of DM. Indeed, the
neuroprotective effect of DM was only observed in the wild-type but not in the
NADPH oxidase-deficient mice, indicating that
NADPH oxidase is a critical mediator of the neuroprotective activity of DM. More importantly, due to its proven safety record of long-term clinical use in humans, DM may be a promising agent for the treatment of degenerative
neurological disorders such as PD.