Comparison between flurbiprofen and its nitric oxide-releasing derivatives HCT-1026 and NCX-2216 on Abeta(1-42)-induced brain inflammation and neuronal damage in the rat

Brain inflammation is an underlying factor in the pathogenesis of Alzheimer's disease (AD) and epidemiological studies indicate that a sustained use of non-steroidal anti-inflammatory drugs (NSAIDs) has a protective effect on the disease. We investigated, in vivo, whether differences exist in the anti-inflammatory and neuroprotective actions of flurbiprofen and its two nitric oxide-donor derivatives, HCT-1026 and NCX-2216, and the ability of these two derivatives to release nitric oxide in the brain. In adult rats injected into the nucleus basalis with preaggregated Abeta(1-42) we investigated by immunohistochemical methods glia reaction, the induction of inducible nitric oxide synthase (iNOS), the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway and the number of choline acetyltransferase (ChAT)-positive neurons and, in naive rats we investigated, by microdialysis, cortical extracellular levels of nitrite. Injection of Abeta(1-42) induced iNOS at the injection site, activated p38MAPK 7 days after injection and brought about an intense microglia and astrocyte reaction along with a marked reduction in the number of ChAT-positive neurones, persisting up to at least up to 21 days. Flurbiprofen, HCT-1026 and NCX-2216 (15 mg/kg) significantly attenuated the Abeta(1-42)-induced glia reaction, iNOS induction and p38MAPK activation 7 days after treatment and astrocytes reaction 21 days after treatment. On an equimolar basis, HCT-1026 resulted the most active agent in reducing the Abeta(1-42)-induced microglia reaction. The cholinergic cell loss was also significantly reduced by 21 days of HCT-1026 treatment. No differences in the body weight were found between the animals treated for 21 days with 15 mg/kg of either HCT-1026 or NCX-2216 and the controls. An oral administration of HCT-1026 (15 mg/kg) or NCX-2216 (100 mg/kg) to naiive rats was followed by significant and long long-lasting increases in cortical nitrite levels. These findings indicate that the addition of a nitric oxide donor potentiates the anti-inflammatory activity of flurbiprofen in a model of brain inflammation.