Jpn. J. Pharmacol. 82 (2), 85-94 (2000)

New Anti-inflammatory Treatment Strategy in Alzheimer's Disease

Kiminobu Sugaya, Tolga Uz, Vinod Kumar and Hari Manev

The Psychiatric Institute, West Side VA Medical Center, Department of Psychiatry, University of Illinois at Chicago,
Chicago, IL 60612, USA

Abstract: Numerous reports have indicated that patients suffering from inflammatory diseases (e.g., arthritis) who take anti-inflammatory medication have a reduced 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 gastrointestinal system from the resultant reduced cytoprotection, selective COX-2 inhibitors are being investigated and tested clinically as potentially better therapeutics for AD patients. However, such drugs may also trigger unwanted effects; for example, the COX-2 inhibitors, which reduce the production of one type of eicosanoids, the prostaglandins, may increase the production of other eicosanoids; i.e., the leukotriene╩B4 (LTB4), which is one of the most potent endogenous chemotactic/inflammatory factors. LTB4 production is initiated by the enzyme 5-lipoxygenase (5-LOX). The expression of the 5-LOX 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 investigated. We propose that the 5-LOX inflammatory cascade may take part in the process of aging-associated neurodegenerative diseases, and we point to the role of 5-LOX in neurodegeneration and discuss its relevance for anti-inflammatory therapy of AD.

Keywords: Inflammation, Cyclooxygenase, 5-Lipoxygenase, Nonsteroidal anti-inflammatory drug, Dementia

Copyrightę The Japanese Pharmacological Society 2000

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