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September 2003

Inflammation and the aging brain
By Dale Kiefer

Microglial cells, which accompany the neuritic plaques of Alzheimer’s disease, are normally dormant. They are activated only in response to inflammation, thus their presence is a sure sign of brain inflammation. Although present in large numbers in the brains of patients with degenerative neurological diseases, such as Huntington’s6 and Alzheimer’s diseases, their numbers are also elevated in otherwise healthy elderly individuals. This implies that a certain degree of neuroinflammation is an ordinary result of nothing more than advanced age.2 Indeed, some scientists have suggested that cognitive decline begins early in the aging process and is an inevitable result of advancing age.7 Controlling inflammation, therefore, could presumably benefit anyone interested in preventing eventual memory loss and cognitive decline.

Dual pathways to inflammation
Just in the last decade, scientists discovered a key enzyme produced by the body in response to inflammatory provocations: cyclooxygenase-2 (better known as COX-2). COX-2 has been identified as an important link in the inflammation cascade. Unlike COX-1, COX-2 is only present in the body during inflammation Research has revealed that cells convert cell membrane phospholipids to arachidonic acid, which serves as a substrate that gives rise, in turn, to two powerful and potentially damaging classes of inflammation mediators, known as eicosanoids: the prostaglandins and leukotrienes. As one researcher noted, “Arachidonic acid release and production of eicosanoids are prerequisites for inflammation”1 The eicosanoids are synthesized from arachidonic acid by the action of two enzymes that form the crux of dual inflammatory pathways: cyclooxygenase (COX) and lipooxygenase (5-LOX).

The COX proteins take two forms: COX-1 and COX-2. The actions of COX-1 are generally beneficial. But the activity of COX-2 is generally harmful. COX-2 inserts an oxygen molecule into arachidonic acid to synthesize prostaglandins, which are powerful triggers of pain and inflammation. 5-LOX converts arachidonic acid into inflammatory leukotrienes.

NSAID medications treat inflammation by blocking the activity of both the COX-2 enzyme and its more benevolent sibling, COX-1. But COX-1 is necessary for stomach lining protection; so interfering with COX-1’s activity can cause gastric disturbances ranging from simple discomfort to dangerous bleeding ulcers. For this reason the new COX-2-inhibitor class of prescription drugs (e.g. Celebrex and Vioxx) has rocketed to popularity. Their more selective action effectively relieves inflammation while minimizing the distressing side effects that are possible with chronic use of NSAIDs.

Researchers are investigating the possibility that anti-inflammatory agents, such as the COX-2 inhibitors, may provide viable therapy not only for Huntington’s, but also for other neuro-degenerative diseases such as Alzheimer’s and Parkinson’s disease. It’s well documented that the COX pathway generates inflammatory prostaglandins. But medical research has largely ignored the potentially damaging effects of 5-LOX, the enzyme that forms the second branch of the dual arachidonic acid inflammation pathways. As a recent study reported, 5-LOX might play a significant role in the pathobiology of aging-associated neuro-degenerative diseases.8

5-LOX generates inflammatory leukotrienes, which are known to be potent inflammatory mediators that play a role in allergic reactions. They may also play a role in ischemia and atherosclerosis.9 Stroke, traumatic brain injury and Alzheimer’s disease have also been linked to the activity of 5-LOX and leukotrienes.2 The results of a recent study indicate that blocking COX-2 while ignoring the effects of 5-LOX may be counter-productive. In fact, using COX-2 inhibitors to block the activity of COX-2 may actually cause 5-LOX levels to increase further, making inflammation worse, rather than better.2 This “rebound” inflammation is evidently caused by shifting arachidonic acid toward synthesis of damaging leukotrienes through the 5-LOX pathway.

An obvious solution to this problem would be the addition of a drug to the anti-inflammatory regimen that can block 5-LOX. Fortunately, such substances exist, although they have only recently come under scrutiny as complements to far more heavily researched NSAIDs and COX-2 inhibitors.

In one 5-LOX inhibition study, researchers speculated, ‘Inhibitors of the two pathways might have additive, or even synergistic neuroprotective effects when used in combination.’ By study’s end, they had concluded that a 5-LOX inhibitor “significantly potentiated the effects of three different COX inhibitors.”2 Their findings suggest, quite simply, that while anti-inflammatory therapy with COX-inhibitors may be neuroprotective, therapy combining both COX and 5-LOX inhibitors should prove considerably more effective.

The promise of anti-inflammatory therapy
The feedback loops in the brain do not allow for simplistic approaches to the treatment of multi-factorial diseases. Not surprisingly, a recent study in the Journal of the American Medical Association found that COX-2 inhibition alone was ineffective in slowing the progression of clinically diagnosed Alzheimer’s disease. It is likely that these results reinforce a growing body of research that dual inflammatory pathway inhibition may be needed to fully realize the promise of anti-inflammatory therapy. While anti-inflammatory therapy may slow progression of some diseases, it may be necessary to begin taking anti-inflammatory agents long before symptoms appear, in order to prevent or reverse the ravages of neurodegenerative diseases.


1. Paris D, et al. AB vasoactivity: an inflammatory reaction. Ann N Y Acad Sci (no date provided) pp.97-108.

2. Klegeris A et al. Cyclooxygenase and 5 lipooxygenase inhibitors protect against mononuclear phagocyte neurotoxicity. Neurobiol of Aging 2002 (23) 787-794.

3. Teismann P, et al. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. PNAS 2003; 100 (9):5473-5478.

4. Pompl PN, et al. A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003; 10.1096/fj.02- 0876fje

5. Scali C, et al. The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo. Neuroscience 2003; 117:909-919.

6. Sapp et al., Early and progressive accumulation of reactive microglial in the Huntington Disease Brain. Neuropathol Exp Neurol 2001; 60(2): 161-172.

7. Jorm AF, et al. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987; 76: 465-479.

8. Uz T, et al. Aging-associated up-regulation of neuronal 5- lipoxygenase expression: putative role in neuronal vulnerability. FASEB 1998; 12: 439-449.

9. Spanbroek R et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. PNAS 2003; 100:12381243.