Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice.
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 5 days. 7-Nitroindazole prevented dose-dependently a significant reduction in dopamine contents of the striatum 5 days 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 5 days. 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.
Yokoyama
Hironori
H
Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78, Sho-machi, Tokushima 770-8505, Japan.
Yano
Ryohei
R
Aoki
Eriko
E
Kato
Hiroyuki
H
Araki
Tsutomu
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004298:Dopamine / Q000378:metabolism; D000077553:Edaravone; D020536:Enzyme Activators / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D017308:Etodolac / Q000627:therapeutic use; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use; D000077340:Fluvastatin; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006719:Homovanillic Acid / Q000378:metabolism; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D007213:Indomethacin / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use
D016861:Cyclooxygenase Inhibitors; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D016166:Free Radical Scavengers; D007191:Indazoles; D007211:Indoles; D018696:Neuroprotective Agents; D011804:Quinolines; D015102:3,4-Dihydroxyphenylacetic Acid; D017308:Etodolac; D000077340:Fluvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D008911:Minocycline; C108475:pitavastatin; D000077553:Edaravone; D000983:Antipyrine; C080122:7-nitroindazole; D004298:Dopamine; D006719:Homovanillic Acid; D007213:Indomethacin