Pathways of inflammatory activation in Alzheimer's disease: potential targets for disease modifying drugs.
In the human brain several cell types are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, prostaglandins and oxygen free radicals. In Alzheimer's disease (AD), signs of an inflammatory activation of microglia and astroglia are present inside and outside amyloid deposits. Cell culture and animal models suggest an interactive relationship between inflammatory activation, reduced neuronal functioning and deposition of amyloid. The activation of inflammation-associated enzymes such as p38 mitogen-activated protein kinase (p38 MAPK) and cycloxygenase-2 (COX-2) is not restricted to glial cells but also found in neurons and may contribute to intraneuronal damage. Epidemiological studies have shown a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. Small clinical trials with non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and diclofenac showed a trend for a disease modifying effect, while clinical trials with steroids did not show a beneficial effect. NSAIDs may not only act on COX-2 but also inhibit COX-1 activity or activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Among promising new strategies to reduce the inflammatory activation in the CNS interfering with intracellular pro-inflammatory pathways has been shown to be effective in various cell culture and animal models. Inhibitors of p38MAPK and PPAR gamma agonists may be suitable agents to suppress inflammatory activation in AD.
Hüll
M
M
Department of Psychiatry, Neurochemistry Research, University of Freiburg, Medical School, Hauptstr. 5, D-79104 Freiburg, Germany. michael_huell@psyallg.ukl.uni-freiburg.de
Lieb
K
K
Fiebich
B L
BL
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology
D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators