Metabolic Brain Disease

, Volume 23, Issue 3, pp 335–349 | Cite as

Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice

  • Hironori Yokoyama
  • Ryohei Yano
  • Eriko Aoki
  • Hiroyuki Kato
  • Tsutomu Araki
Original Paper


The biochemical and cellular changes that occur following the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson’s disease(PD). There is growing evidence indicating that reactive oxygen species (ROS), reactive nitrogen species (RNS) and inflammation are a major contributor to the pathogenesis and progression of PD. Hence, we investigated whether 7-nitroindazole [neuronal nitric oxide synthase (nNOS) inhibitor], edaravone (free radical scavenger), minocycline [inducible NOS (iNOS) inhibitor], fluvastatin [endothelial NOS (eNOS) activator], pitavastatin (eNOS activator), etodolac [cyclooxygenase-2 (COX-2) inhibitor] and indomethacin (COX inhibitor) can protect against MPTP neurotoxicity in mice under the same conditions. For the evaluation of each drug, the levels of dopamine, DOPAC and HVA were quantified using HPLC with an electrochemical detector. Four administrations of MPTP at 1-h intervals to mice produced marked depletion of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanilic acid) in the striatum after 5days. 7-Nitroindazole prevented dose-dependently a significant reduction in dopamine contents of the striatum 5days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin, pitavastatin, etodolac and indomethacin did not show the neuroprotective effect on MPTP-induced striatal dopamine, DOPAC and HVA depletions after 5days. The present study demonstrates that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared with the production of ROS, the overexpression of iNOS, the modulation of eNOS and the involvement of inflammatory response. Thus our pharmacological findings provide further information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.


Parkinson’s disease MPTP Reactive oxygen species Reactive nitrogen species Inflammation Dopaminergic system Mice 


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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Hironori Yokoyama
    • 1
  • Ryohei Yano
    • 1
  • Eriko Aoki
    • 1
  • Hiroyuki Kato
    • 2
  • Tsutomu Araki
    • 1
  1. 1.Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of TokushimaTokushimaJapan
  2. 2.Department of Neurology, Organized Center of Clinical MedicineInternational University of Health and WelfareTochigiJapan

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