A novel neuroprotective agent with antioxidant and nitric oxide synthase inhibitory action.
N(alpha)-vanillyl-N(omega)-nitroarginine (N - 1) that combines the active functions of natural antioxidant and nitric oxide synthase inhibitor was developed for its neuroprotective properties. N - 1 exhibited protective effects against hydrogen peroxide-induced cell damage and the inhibitory effect on nitric oxide 'NO' production induced by calcium ionophore in NG 108-15 cells. N - 1 inhibited the constitutive NOS isolated from rat cerebellar in a greater extent than constitutive NOS from human endothelial cells. Low binding energy (-10.2 kcal/mol) obtained from docking N - 1 to nNOS supported the additional mode of action of N - 1 as an nNOS inhibitor. The in vivo neuroprotective effect on kainic acid-induced nitric oxide production and neuronal cell death in rat brain was investigated via microdialysis. Rats were injected intra-peritonially with N - 1 at 75 micromol/kg before kainic acid injection (10 mg/kg). The significant suppression effect on kainic acid-induced NO and significant increase in surviving cells were observed in the hippocampus at 40 min after the induction.
Vajragupta
Opa
O
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Mahidol University, Bangkok, Thailand. pyovj@mahidol.ac.th
Boonyarat
Chantana
C
Murakami
Yukihisa
Y
Tohda
Michihisa
M
Musatmoto
Kinzo
K
Olson
Arthur J
AJ
Watanabe
Hiroshi
H
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D004791:Enzyme Inhibitors; C515156:N(alpha)-vanillyl-N(omega)-nitroarginine; D018696:Neuroprotective Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D007608:Kainic Acid