Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease.
Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada.
Andis
A
Klegeris
Patrick L
PL
McGeer
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000209:etiology; D017628:Microglia / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011451:Prostaglandin-Endoperoxide Synthases