New anti-inflammatory treatment strategy in Alzheimer's disease

Numerous reports have indicated that patients suffering from inflammatory d iseases (e.g., arthritis) who take anti-inflammatory medication have a redu ced risk of developing Alzheimer's disease (AD). Thus, the first generation of anti-inflammatory cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, have been tested as potential therapeutics in AD. Because the inhibition of COX-1 is also known to cause tissue damage in the gastrointe stinal system from the resultant reduced cytoprotection, selective COX-2 in hibitors are being investigated and tested clinically as potentially better therapeutics for AD patients. However, such drugs may also trigger unwante d effects; for example, the COX-2 inhibitors, which reduce the production o f one type of eicosanoids, the prostaglandins, may increase the production of other eicosanoids; i.e., the leukotriene B-4 (LTB4), which is one of the most potent endogenous chemotactic/inflammatory factors. LTB4 production i s initiated by the enzyme 5-lipoxygenase (5-LOX). The expression of the 5-L OX gene is upregulated during neurodegeneration and with aging. In spite of the fact that 5-LOX and leukotrienes are major players in the inflammation cascade, their role in AD pathobiology/therapy has not been extensively in vestigated. We propose that the 5-LOX inflammatory cascade may take part in the process of aging-associated neurodegenerative diseases, and we point t o the role of 5-LOX in neurodegeneration and discuss its relevance for anti -inflammatory therapy of AD.