Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity.
Beta amyloid (Abeta) is implicated in Alzheimer's disease (AD). Abeta(1 - 42) (5, 10, or 20 microM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures. L-NOARG and SMTC (both at 10 or 100 microM) - type I NOS inhibitors - reduced cellular NO release in the absence of Abeta(1 - 42). At 100 microM, both drugs decreased cell viability. L-NIL (10 or 100 microM), and 1400W (1 or 5 microM) - type II NOS inhibitors - reduced NO release and improved viability when either drug was administered up to 4 h post Abeta(1 - 42) (10 microM) treatment. L-NOARG and SMTC (both at 10 or 100 microM) were only able to decrease NO release. Carboxy-PTIO or Trolox (both at 10 or 100 microM) - a NO scavenger and an antioxidant, respectively - increased viability when administered up to 1 h post Abeta(1 - 42) treatment. Either L-NIL (50 microM) or 1400W (3 microM) and Trolox (50 microM) showed synergistic actions. Peroxynitrite (100 or 200 microM) reduced cell viability. Viabilities were improved by L-NIL (100 microM), 1400W (5 microM), carboxy-PTIO (10 or 100 microM), and Trolox (10 or 100 microM). Hence, the data show that Abeta(1 - 42) induced NO release in neurons and glial cells, and that Abeta neurotoxicity is, at least in part, mediated by NO. NO concentration modulating compounds and antioxidant may have therapeutic importance in neurological disorders where oxidative stress is likely involved such as in AD.
Law
A
A
Douglas Hospital Research Centre, 6875 boulevard Lasalle, Verdun, Québec, Canada, H4H 1R3.
Gauthier
S
S
Quirion
R
R
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001565:Benzoates; D002839:Chromans; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; C090663:N(6)-(1-iminoethyl)lysine; D018696:Neuroprotective Agents; D009566:Nitrates; D016877:Oxidants; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D019335:Nitroarginine; C039642:peroxynitric acid; D002956:Citrulline; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D013890:Thiourea; D008239:Lysine; C086717:S-methylthiocitrulline; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid