New anti-inflammatory treatment strategy in Alzheimer's disease.
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.
Sugaya
K
K
The Psychiatric Institute, West Side VA Medical Center, Department of Psychiatry, University of Illinois at Chicago, 60612, USA.
Uz
T
T
Kumar
V
V
Manev
H
H
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D016207:Cytokines / Q000502:physiology; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology
D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases