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Beta amyloid (Aβ) is implicated in Alzheimer's disease (AD). Aβ1–42 (5, 10, or 20 μM) 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 μM) – type I NOS inhibitors – reduced cellular NO release in the absence of Aβ1–42. At 100 μM, both drugs decreased cell viability. L-NIL (10 or 100 μM), and 1400W (1 or 5 μM) – type II NOS inhibitors – reduced NO release and improved viability when either drug was administered up to 4 h post Aβ1–42 (10 μM) treatment. L-NOARG and SMTC (both at 10 or 100 μM) were only able to decrease NO release. Carboxy-PTIO or Trolox (both at 10 or 100 μM) – a NO scavenger and an antioxidant, respectively–increased viability when administered up to 1 h post Aβ1–42 treatment. Either L-NIL (50 μM) or 1400W (3 μM) and Trolox (50 μM) showed synergistic actions. Peroxynitrite (100 or 200 μM) reduced cell viability. Viabilities were improved by L-NIL (100 μM), 1400W (5 μM), carboxy-PTIO (10 or 100 μM), and Trolox (10 or 100 μM). Hence, the data show that Aβ1–42 induced NO release in neurons and glial cells, and that Aβ 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. British Journal of Pharmacology (2001) 133, 1114–1124; doi:10.1038/sj.bjp.0704179 |
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