5 replies to this topic

[NDM]

I provide below two quotes, which, if jointly read, suggest that aspirin might have major uses in fighting neuro-inflammation, a condition that can cause or be caused by diverse vectors such as bacterial and viral infections, alcoholism, and neurodegenerative diseases. For many of us, aspirin may be the cheapest nootropic, if we loosely define the latter term to include any substance which either improves or else maintains brain functioning (given aging, maintenance is a form of improvement).

The first quote is from Wikipedia
"There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2."

The second quote is the abstract of an "in press" article (importantly, an OPINION PIECE) from Trends in Pharmacological Sciences
doi:10.1016/j.tips.2009.01.002

"Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component."

I hope that the cognoscendi on this forum will qualify my enthusiasm, set the "discovery" in the appropriate context, and, most importantly, make suggestions about its practical implications for those of us in search for better health, faster brains, and longer lives.

[niner]

Bayer: The Wonder Drug that Works Wonders... (I think that was their slogan). There's something to it; aspirin is a hell of a compound. The major downside is that COX-1 inhibition can lead to a loss of protective prostaglandins that are involved in protection of GI tissues. This can lead to GI bleeds and associated complications that hospitalize and kill people on a very regular basis. This is a downside of most NSAIDS, not just aspirin. An important thing to know would be what concentration of aspirin (or what degree of COX-1 inhibition) is needed to get the neuroprotective effect? Is it low enough that you could take that amount of aspirin or other COX-1 inhibitor for an extended period without likely injury? There have been some studies of aspirin against Alzheimer's disease, with varying results. A recent study sounds as though it has seen positive results, but I haven't seen the paper. Here's a link to it, though it's behind a paywall. Some of you might have access through school or work.

http://linkinghub.el...4422(07)70296-X

[NDM]

I've done some further research and selected the three abstracts below. The last one seems to confirm our fears: (1) the effect of NSAIDS such as aspirin is dose-dependent and (2) there are side effects.


neuro-inflammation undermines synaptic plasticity

Trends in Pharmacological Sciences, Volume 29, Issue 8, 402-412, 1 August 2008 doi:10.1016/j.tips.2008.06.005

Review


Neuroinflammation and synaptic plasticity: theoretical basis for a novel, immune-centred, therapeutic approach to neurological disorders

Abstract
The fascinating capacity that the central nervous system (CNS) has for encoding and retaining memories is thought to be based on activity-dependent forms of synaptic plasticity. The CNS and the immune systems are known to be engaged in an intense bidirectional crosstalk, and glial cells are now viewed as a crucial third element of the synapse. In this opinion article, we review the principal mechanisms by which the immune system, and in particular immune diffusible mediators, influences synaptic transmission and the induction of brain plastic phenomena. Thereafter, we consider the potential implications of inflammation-related overexpression of diffusible mediators in the disruption of synaptic plastic processes and neuronal networks functioning during human neurological diseases. Finally, we propose that a more accurate characterization of the mechanisms underlying the immune-mediated control of synaptic plasticity could represent, in the future, the basis for the development of a novel immune-centred therapeutic approach to neurological disorders.



see also


Trends in Immunology
Volume 29, Issue 8, August 2008, Pages 357-365
Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

AbstractNeurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases.

and finally
NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies
Neurobiology of Aging, 2007, Volume 28, Issue 5, Pages 639-647

<H2 class=style1>Abstract</H2>This review reports correlations between four independent fields related to inflammation and Alzheimer disease: fundamental pathology, epidemiology, transgenic animal studies and clinical trials. Activated microglia, along with a spectrum of inflammatory mediators, have been identified in association with the lesions of Alzheimer disease (AD), suggesting that antiinflammatory agents such as NSAIDs should protect against the disease. In multiple epidemiological investigations testing this hypothesis, a significant risk reduction, or a trend towards such a reduction has been observed in long term as opposed to short term users of traditional NSAIDs. In studies where such NSAIDs have been administered to AD transgenic mice, a dose dependent reduction in pathology was observed. The selective C0X-2 inhibitors were ineffective. Results of clinical investigations have so far been disappointing but have nevertheless correlated with fundamental pathological findings and with transgenic mouse results. Four clinical trials using selective COX-2 inhibitors failed which is in keeping with the animal results and is consistent with pathological findings demonstrating that COX-1 and not COX-2 is the appropriate target in activated human microglia. A low dose trial of the traditional NSAID naproxen also failed, but pilot trials using therapeutically established doses of indomethacin and diclofenac/misoprostol showed promise. Further clinical investigations with relatively high doses of traditional NSAIDs might be warranted, although significant side effects should be anticipated.

[FunkOdyssey]

I am more interested in eliminating causes of neuroinflammation rather than intervening downstream in the cause -> effect cascade by inhibiting the inflammatory response. However, if for some reason you are unable to identify or eliminate the cause of the inflammation, aspirin or better yet, ibuprofen (similar benefits without compromising platelet function) is the next best thing. A recent study showed that individuals that used ibuprofen even once weekly had dramatically reduced risk of parkinson's disease.

[luv2increase]

I believe that inhibiting COX-2 is second to inhibiting 5-LOX.

I believe if one wants to truly utilize efficaciously the inhibition of these two enzymes, one must partake in the supplementation of actives which will do so.

We have to get rid of those darn leukotrienes! If you want to successfully age at a very turtle-like rate then one will do so.


AKBA to target 5-LOX & Curcumin to target COX-2. It doesn't get any simpler than this ladies and gents




Happy aging...

luv2increase

[NDM]

wikipidia's entry for ibuprofen is not that positive:
"Ibuprofen is an NSAID which is believed to work through inhibition of cyclooxygenase (COX), thus inhibiting prostaglandin synthesis. There are at least 3 variants of cyclooxygenase (COX-1, COX-2, and COX-3). Ibuprofen inhibits both COX-1 and COX-2. It appears that its analgesic, antipyretic, and anti-inflammatory activity are achieved principally through COX-2 inhibition; whereas COX-1 inhibition is responsible for its unwanted effects on platelet aggregation and the GI mucosa. The role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain and different compounds cause different degrees of analgesia and gastric damage.^[13]"

However, the fact that it works for Parkinson prevention even in small weekly doses suggests that it would be better to, say, take aspirin 4-5 days a week, and ibuprofen in the remaining 2-3, rather than to stick with the same NSAID all the days. I would like though, to see more information on exactly how the mechanisms of action of aspirin and ibuprofen differ. It is somewhat bizzare that although they are widely used, we still speak in terms of "it is believed that their mechanism of action is ..."

A related issue is to sum up all the anti-COX substances one is ingesting - as far as I can remember, curcumin, for example, is both a COX and a LOX inhibitor. The nice thing about aspirin is that, unlike AOR's curcumin, it is very cheap.