Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity

I Beta amyloid (A beta) is implicated in Alzheimer's disease (AD). A beta (1) (42) (5, 10, or 20 muM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures. 2 L-NOARG and SMTC (both at 10 or 100 muM) - type I NOS inhibitors - reduced cellular NO release in the absence of A beta (1) (42). At 100 muM, both drugs decreased cell viability. 3 L-NIL (10 or 100 pm), and 1400W (1 or 5 muM) type II NOS inhibitors - reduced NO release and improved viability when either drug was administered up to 4 h post A beta (1) (42) (10 muM) treatment. L-NOARG and SMTC (both at 10 or 100 muM) were only able to decrease NO release. Carboxy-PTIO or Trolox (both at 10 or 100 muM) - a NO scavenger and an antioxidant, respectively increased viability when administered up to 1 h post A beta (1) (42) treatment. Either L-NIL (50 muM) or 1400W (3 muM) and Trolox (50 muM) showed synergistic actions. 4 Peroxynitrite (100 or 200 muM) reduced cell viability. Viabilities were improved by L-NIL (100 muM), 1400W (5 muM), carboxy-PTIO (10 or 100 muM), and Trolox (10 or 100 muM). 5 Hence, the data show that A beta (1) (42) induced NO release in neurons and glial cells, and that A beta 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.