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

• Published in: Metabolic brain disease 2008-09, Vol.23 (3), p.335-349
• Main Authors: Yokoyama, Hironori, Yano, Ryohei, Aoki, Eriko, Kato, Hiroyuki, Araki, Tsutomu
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Animals; Antipyrine - analogs & derivatives; Antipyrine - therapeutic use; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cyclooxygenase Inhibitors - therapeutic use; Dopamine - metabolism; Enzyme Activators - therapeutic use; Enzyme Inhibitors - therapeutic use; Etodolac - therapeutic use; Fatty Acids, Monounsaturated - therapeutic use; Free Radical Scavengers - therapeutic use; Homovanillic Acid - metabolism; Indazoles - therapeutic use; Indoles - therapeutic use; Indomethacin - therapeutic use; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Minocycline - therapeutic use; MPTP Poisoning - prevention & control; Neurology; Neuroprotective Agents - therapeutic use; Neurosciences; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III - metabolism; Oncology; Original Paper; Quinolines - therapeutic use
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-008-9096-3

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.