1 b-Amyloid peptide (Ab), a 39 ± 43 amino acid peptide, is believed to induce oxidative stress and in¯ammation in the brain, which are postulated to play important roles in the pathogenesis of Alzheimer's disease. Ferulic acid is an antioxidant and anti-in¯ammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against Ab toxicity in vivo was examined. 2 Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, Ab1-42 (410 pmol) was administered via intracerebroventricular injection. 3 Injection of control mice with Ab1-42 impaired performance on the passive avoidance test (35% decrease in step-through latency), the Y-maze test (19% decrease in alternation behaviour), and the water maze test (32% decrease in percentage time in platform-quadrant). In contrast, mice treated with ferulic acid prior to Ab1-42 administration were protected from these changes (9% decrease in step-through latency; no decrease in alternation behaviour; 14% decrease in percentage time in platform-quadrant). Ab1-42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid. 4 In addition, Ab1-42 increased immunoreactivities of the astrocyte marker glial ®brillary acidic protein (GFAP) and interleukin-1b (IL-1b) in the hippocampus, eects also suppressed by pretreatment with ferulic acid. 5 Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL-1b immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. A slight (8%) decrease in alternation behaviour was observed on day 14. 6 These results demonstrate that long-term administration of ferulic acid induces resistance to Ab1-42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimer's disease.

The pathogenesis of nonalcoholic steatohepatitis (NASH) is unclear, despite epidemiological data implicating FFAs. We studied the pathogenesis of NASH using lipoapoptosis models. Palmitic acid (PA) induced classical apoptosis of hepatocytes. PA-induced lipoapoptosis was inhibited by acyl-CoA synthetase inhibitor but not by ceramide synthesis inhibitors, suggesting that conversion products other than ceramide are involved. Phospholipase A 2 (PLA 2 ) inhibitors blocked PA-induced hepatocyte death, suggesting an important role for PLA 2 and its product lysophosphatidylcholine (LPC). Small interfering RNA for Ca 21 -independent phospholipase A 2 (iPLA 2 ) inhibited the lipoapoptosis of hepatocytes. PA increased LPC content, which was reversed by iPLA 2 inhibitors. Pertussis toxin or dominant-negative Ga i mutant inhibited hepatocyte death by PA or LPC acting through G-protein-coupled receptor (GPCR)/Ga i . PA decreased cardiolipin content and induced mitochondrial potential loss and cytochrome c translocation. Oleic acid inhibited PA-induced hepatocyte death by diverting PA to triglyceride and decreasing LPC content, suggesting that FFAs lead to steatosis or lipoapoptosis according to the abundance of saturated/unsaturated FFAs. LPC administration induced hepatitis in vivo. LPC content was increased in the liver specimens from NASH patients. These results demonstrate that LPC is a death effector in the lipoapoptosis of hepatocytes and suggest potential therapeutic values of PLA 2 inhibitors or GPCR/ Ga i inhibitors in

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