I'm not sure this article is readily available to I'll post a portion here:

"The interest in exploring a neuroprotective role for NSAIDs is based on a host of recent studies providing evidence that inflammation resulting from a local immune reaction in affected regions of the brain can contribute to PD."....."In agreement with findings from a few other epidemiologic studies, our group has recently shown that functionally active polymorphisms in the promoters of genes encoding the inflammatory cytokines TNF-α and IL-1β may contribute to PD risk [8–10]." From:

Future Neurology
March 2008, Vol. 3, No. 2, Pages 107-111
(doi:10.2217/14796708.3.2.107)

Can anti-inflammatory agents protect against Parkinson’s disease?
Beate Ritz*, Angelika D Wahner*, Yvette Bordelon* & Jeff M Bronstein*

Parkinson’s disease (PD) is a chronic disease of multifactorial etiology likely arising from an interplay of environmental factors, inherited genetic susceptibility and age-related factors that decrease cell fitness and resilience to stress. Despite its complex etiology, a growing body of experimental and epidemiologic evidence now suggests that a certain degree of protection against PD may be provided by something as simple as regular use of aspirin or other commonly used drugs known as NSAIDs.

Evidence is accumulating that inflammation in brain tissue contributes to the pathogenesis of PD, and anti-inflammatory drugs may be capable of preventing or reducing neuronal degeneration caused by neuroinflammation. In this editorial we will primarily assess existing human epidemiologic evidence, but also summarize contributions from in vivo and in vitro studies of aspirin/NSAIDs in PD, each an important step in gaining an understanding of whether and how NSAIDs may protect some at-risk individuals against PD.

The interest in exploring a neuroprotective role for NSAIDs is based on a host of recent studies providing evidence that inflammation resulting from a local immune reaction in affected regions of the brain can contribute to PD.

Specifically, the hallmarks of chronic inflammation; activated microglia, glial cell-mediated inflammatory events and the production of proinflammatory chemical mediators, have been observed in animal models of PD, in the brains of deceased PD patients and in human in vivo PET studies [1–6]. For example, in both nonprimate 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) experimental models and in autopsied brains of three human MPTP victims, activated microglia were observed in the substantia nigra pars compacta (SNpc), suggesting that an active inflammatory process may have been contributing to nigral cell death and – for the latter – that it continued long after the primary toxic insult occurred [7].

In agreement with findings from a few other epidemiologic studies, our group has recently shown that functionally active polymorphisms in the promoters of genes encoding the inflammatory cytokines TNF-α and IL-1β may contribute to PD risk [8–10].

Besides elucidating a role for neuroinflammation in PD pathogenesis, some studies have also made more specific inquiries into the role of anti-inflammatory drugs in neurodegeneration [11–15]. NSAIDs are inhibitors of proinflammatory COX enzymes, and studies have implicated COX in the pathogenesis of PD. COX-2 is upregulated in the dopaminergic neurons of both PD patients and mouse models of PD [1,15,16]. In the latter, degeneration of dopaminergic neurons was attenuated by treatment with COX-2 inhibitors and in COX-2gene knockout mice [17,18]. COX-2 inhibition also prevented the formation of potentially toxic dopamine-quinones in MPTP-treated mice [16,19].

The deleterious consequences of dopamine-quinone production include the depletion of vital antioxidants, such as glutathione, and the accumulation of α-synuclein protofibrils, a proposed key event in PD pathogenesis [16].

Thus, it seems reasonable to hypothesize that COX inhibitors, such as NSAIDs, interfere with COX-2 upregulation or its increased activity in SNpc dopaminergic neurons and the subsequent oxidative stress cascades, thereby possibly playing an important role in progressive dopaminergic neuron loss in PD.

Other experimental investigations suggest some alternative mechanisms by which NSAIDs may exert their neuroprotective effects. For example, NSAIDs are reported to block activation of the transcription factor NF-κB, which has been linked to oxidative stress and the induction of apoptosis in PD [20]. One study found a 70-fold increase in NF-κB translocation in the mesencephalic dopamine neurons at post-mortem of patients with idiopathic PD compared with controls [6]. Anti-inflammatory drugs block the activation of NF-κB downstream from activated glutamate receptors, reducing striatal dopamine depletion and dopaminergic neuron loss induced by MPTP in cultured neurons [12–15]. Indeed, nonaspirin NSAIDs such as ibuprofen can attenuate glutamate toxicity toward dopaminergic neurons [21,22]. Finally, NSAIDs are effective scavengers of hydroxyl radicals and nitric oxide, which may play critical roles in PD pathogenesis [13,14,23,24].

The current epidemiologic literature is somewhat equivocal, but convergent evidence suggests that aspirin and nonaspirin NSAIDs may act as neuroprotective agents in PD. We recently published our findings from a population-based case–control study conducted in rural California in which aspirin and nonaspirin NSAID use protected against PD [25]. Specifically, we found that PD risk was halved among regular (≥2 pills/week) nonaspirin NSAID users who reported 2 or more years of use during middle age, while regular long-term use of aspirin was accompanied by a similar size risk reduction in women only. Our study confirmed first reports of a possible protection due to anti-inflammatory drug use published 4 years earlier for the Health Professionals Follow-up and Nurses’ Health Study cohorts. Similar to our results, these authors had observed a halving of risk in regular users (≥2 tablets/week) of nonaspirin NSAIDs as well as regular (daily) users of aspirin [21]. Another study conducted by the same group in the American Cancer Society cohort, however, suggested protection only for daily users of one specific NSAID, ibuprofen, and not aspirin [18]. A much smaller Dutch cohort found no association or a small risk increase among ever users of NSAIDs, but only six PD cases reported use of these medications for more than 1 year [26].

In addition to our own study, reports from five other case–control studies examining PD and NSAID use have been published in the past 2 years. Mayo clinic researchers analyzing prescription data from medical records described a protective association similar in size to the cohort and our studies for nonaspirin NSAIDs, but no protection for aspirin users [27] . A similar approach was employed by a Seattle study that relied on pharmacy records within a health maintenance cooperative to assess NSAID prescription and over-the-counter (OTC) pills [28]. This research suggested a small protective association resulting in a possible 10–25% risk reduction for aspirin and, to a lesser degree, for ibuprofen users only during the period of 1977 to 1992, when OTC use of these medications was limited. A family based case–control study did not find any association for current or relatively short-term use of any of the commonly used NSAIDs, including aspirin [29]. Reports are also available for two much larger case–control studies. In Britain, researchers studied 1258 PD cases and 6638 controls listed in the UK General Practice Research Database, and evaluated prescription NSAID use [30]. They found a small increase in risk for prescription aspirin ever and current use while nonaspirin NSAIDs appeared protective only in men and when taken for more than 3 years or at high doses. A very recently published US-pooled analysis drawing from 1186 PD cases and 928 controls suggested some risk reduction (20–30%) with ever OTC nonaspirin NSAID use [31]. In contradiction to the British study but in support of our own and the larger US based cohort studies, associations were stronger and more consistently observed in women. Unfortunately this latest study did not have any data on aspirin use available for analysis.

Thus, while epidemiologic information evaluating the possible neuroprotective role of NSAIDs is rapidly accumulating, study results are somewhat inconsistent. Studies differed as to the data sources employed (self-report, pharmaceutical databases and medical records), the type of medication assessed (OTC versus prescription or both, aspirin and nonaspirin NSAIDs or specific medications) and, importantly, the time frame for which the medication use was assessed. Each of these methods carries advantages and disadvantages, and differences in methodology can provide new insights. For example, studies that utilize pharmaceutical databases avoid the problem of subject recall but may not accurately reflect intake of drugs with widespread OTC use, particularly in the USA where NSAIDs are frequently purchased over the counter. The study conducted in the Seattle Health Maintenance Cooperative System illustrates this problem: a survey cited by the authors showed that 85% of all ibuprofen medications obtained without a doctor’s prescription were recorded in the system’s pharmacy database prior to 1990, but only approximately 30% of all aspirin use was recorded [28]. Conversely, while studies based on self-reported data better capture both OTC and prescription NSAID use, and can also be used to assess extended and lifetime use, they are more susceptible to misreporting and flawed recall. There is some evidence that recall of NSAID use is at least fair, for example, studies evaluating NSAID self-reporting found little over- and under-reporting of prescription NSAID usage [32], however recall of longer term OTC use has not been validated. It is somewhat reassuring that regular users, the group that may benefit the most from the anti-inflammatory aspects of the drugs, are expected to better recollect their use than sporadic users. Nevertheless, for future epidemiologic studies it is important to remember that as those with PD become more aware of a potential protective link between NSAID use and PD, recall and reporting among cases may start to differ from that of unaffected controls and, thus, bias self-reports of use.

Studies also evaluated varying lengths and age/time windows of NSAID use, including lifetime use, medications taken shortly before diagnosis and current use. This discrepancy in timing of NSAID use might have affected study results if NSAIDs’ potential neuroprotective effects are dependent on the life epoch during which exposure occurred, or on the temporal proximity of NSAID exposure to a toxic insult that initiates neuroinflammatory responses. Indeed, there is evidence that neuroinflammation is a self perpetuating reaction that can last for years, as shown by the presence of indices of neuroinflammation in the substantia nigra of MPTP patients as long as 16 years after the original MPTP exposure [7]. Thus, studies assessing shorter term use, use at older age or use during short windows prior to disease onset, may be missing the most relevant time frames for arresting the inflammatory process. For example, this might explain the failure to detect a protective effect in some studies [26,29]. Evaluating current use is especially problematic when studying NSAID use in the context of PD since the preclinical phase of PD is estimated to be long [33,34] and cases may increase pain reliever use in the years leading up to actual diagnosis as a result of preclinical PD. Thus, current use is unlikely to reflect past use, especially among PD cases. It is therefore important that investigators lag (truncate) NSAID exposure at least by 2–7 years before PD diagnosis/index date to account for increasing preclinical use by cases, and studies that include prevalent PD cases need to consider a much longer time frame.

http://www.futuremedicine.com/doi/fu...796708.3.2.107