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ﾊ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