Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase

FASEB J. 2004 Mar;18(3):589-91. doi: 10.1096/fj.03-0983fje. Epub 2004 Jan 20.


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.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / adverse effects*
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / antagonists & inhibitors
  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Coculture Techniques
  • Dextromethorphan / pharmacology
  • Dextromethorphan / therapeutic use*
  • Dopamine / metabolism
  • Drug Evaluation, Preclinical
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidases / antagonists & inhibitors*
  • NADPH Oxidases / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Oxidative Stress / drug effects
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / pathology
  • Parkinsonian Disorders / prevention & control*
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology


  • Antioxidants
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Dextromethorphan
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • NADPH Oxidases
  • Dopamine