P L McGeer

..NSAIDs inhibit the production of prostaglandin inflammatory mediators, but powerful new therapeutic agents might be developed by targeting more critical inflammatory mechanisms, especially the complement system...

..We investigated whether a similar situation may occur in Lyme neuroborreliosis...

..In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases...

..Even in vertebrates, however, the innate immune system is the first line of defense. Much more needs to be learned about the operation of the innate immune system in health and disease. Arch Neurol. 2000...

..The mechanism is unknown but could have important implications regarding the cause of Parkinson's disease and possible approaches to therapy...

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..Accordingly, COX-2 inhibitors may reduce the degree of inflammation and protect against future cardiovascular events...

..65, P=0.0019). A significant increase was not found for the IL-alpha T genotype (chi(2)=1.32, P=0.23), although there was a trend towards more frequent expression of the T allele...

..Inhibitors of mediators closer to the core processes might offer even greater therapeutic promise. Some theoretical opportunities are suggested, based on intervention in the action of the above mentioned mediators...

..The complement system, microglia and cytokines are key components. This review summarizes the present state of knowledge on the immune system elements found in AD brain...

..Such information could lead to strategies for therapeutic intervention in the early stages of such disorders...

..These results emphasise that the appropriate target for NSAID trials in AD is COX-1, but they also indicate that there would be no contraindication to the use of those traditional NSAIDs which have mixed COX-1/COX-2 inhibiting activity...

..Because both pro- and anti-inflammatory activation of immune cells are possible, stimulating the phagocytic action of microglia while simultaneously stimulating anti-inflammatory activity might be beneficial in AD...

..Further research concerning glial reactions in PD may lead to disease-modifying therapeutic approaches...

..Thus, full therapeutic doses of NSAIDs, or combinations of anti-inflammatory agents, are needed to achieve the suggested neurological benefits...

..Further clinical investigations with relatively high doses of traditional NSAIDs might be warranted, although significant side effects should be anticipated...

..Future directions should include a search for other inflammatory mediators in AD and exploitation of current knowledge to improve available treatments...

..Identification of biomarkers for premortem diagnosis would be helpful in management as well as in revealing the true etiology...

..FGFR-1 immunoreactivity was also detected in many of the residual SN neurons in most of the idiopathic PD cases. These results indicate that FGFR-1 immunoreactivity, and possibly FGF binding activity, is retained in DA neurons in PD...

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..A larger dose (10 mg/kg) THA had no significant effect. The results are discussed in terms of THA's binding to various elements of the NMDA/sigma receptor complex and reported data on such binding are confirmed...

..The presence of ICAM-1-positive reactive astrocytes in Parkinson disease and MPTP-treated monkeys is indicative of a sustained inflammatory process and suggests that antiinflammatory agents may have a place in PD therapy...

..We conclude that brain has a robust capacity to synthesize cholesterol which appears to be unaffected by AD pathology...

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..Because CRP is a complement activator, and activated complement attacks cells in plaque tissue, these data provide evidence of a self-sustaining autotoxic mechanism operating within the plaques as a precursor to thrombotic events...

..These data indicate that inflammatory stimuli may increase extracellular glutamate while antiinflammatory drugs decrease it...

..Ret expression by microglia was confirmed by immunoblot analysis on the human THP-1 macrophage type cell line. However, these cells did not express the mRNA for GDNFRalpha, the other component of the GDNF receptor complex...

..Reliable mRNA values may be obtained from postmortem brain with long autolysis times provided the tissue has been kept in the cold, and from frozen tissues for 1-2 h after thawing...

..Glycine appeared to potentiate the effect of high doses of quinolinic acid on ChAT and the other pretreatments tested (dextrorphan, dextromethorphan, 4-acetylpyridine) had no significant effect...

..These data indicate that IL-1alpha and IL-6 can, under appropriate circumstances, protect neurons from oxidative damage in addition to their well-known action of stimulating inflammation...

..The results obtained may help to define the commonality of the Guam disease with other tangle forming disorders and may help in monitoring the epidemiological changes that are taking place...

..Therapeutic strategies for the treatment of AD based on tg mouse models that overexpress Abeta may be limited in their application...

..Capillary staining for NF-kappa B was weak and did not differ significantly between affected and unaffected areas. These results suggest that enhanced expression of astrocytic NF-kappa B occurs in cerebral infarcted areas...

..Since PK 11195 readily enters the brain, it may be beneficial in treating central as well as peripheral inflammatory diseases...

..It is suggested that inhibition of monocyte cytotoxicity might be responsible for the apparent beneficial effects of NSAIDs in Alzheimer's disease...

..As such, they may be prime targets for therapeutic intervention...

..There was no difference between AD and control cases in the staining of glial cells and vascular walls. These results suggest that enhanced expression of neuronal NF-kappa B occurs in areas affected by AD pathology...

..This transplantation of cultured human fetal cells to an animal model may provide the necessary basic experimental system for assessing the possible utility of human neuronal transplants...

..This ApoE4-specific enhancement of complement activation by A beta may relate to its role in increasing the risk of late-onset AD...

..These data indicate that it is primarily the classical, not the alternative pathway, that is activated in plaques and that key inhibitors are not upregulated to defend against this activation...

..These findings suggest that activated astrocytes may become neurotoxic when stimulated by IFN-gamma and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases...

..From a therapeutic point of view it is desirable to find methods of tipping the balance towards an anti-inflammatory state for both types of glia...

..5 Specific CB2 receptor ligands could be useful anti-inflammatory agents, while avoiding the neurotoxic and psychoactive effects of CB1 receptor ligands such as Delta(9)-THC...

..They provide further evidence of an inflammatory response of brain tissue in Alzheimer disease. The microglia were found to make up 9-12% of the total glial population in gray matter and 7.5-9% in white matter...

..Combined observation of these markers in diseased brain tissue can provide clues as to the stage of the pathology being observed...

..Taken in conjunction with evidence of a neuroprotective effect of COX-2 inhibitors in certain animal models and in organotypic cultures, the data are supportive of a possible future role for COX-2 inhibitors in the treatment of ALS...

..Such mechanisms could contribute to the pathogenesis of neurodegenerative disorders, including Alzheimer's disease...

..Overall, the data indicate that effectiveness of degradation by neprilysin may be a key factor in determining whether Abeta deposits develop...

..The colocalization of the kinase Cki delta and its apparent substrate tau suggests a function for Cki delta in the abnormal processing of tau...

..These results suggest that human microglial cells are capable of adhering to and phagocytosing post mortem AD plaque material but activation may be necessary. Astrocytes may further enhance the process...

..These data suggest that antagonists of cytokine receptors, as well as inhibitors of their intracellular pathways may be effective anti-inflammatory agents...

..They suggest that PPIs combined with NSAIDs may be effective in the treatment of a broad spectrum of neurodegenerative diseases associated with activated microglia...

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..Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy...

..We found S- but not R-enantiomers to be protective at low concentrations, which is consistent with a COX-dependent mechanism...

..We found both to be partially protective in a concentration-dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases...

..Anti-inflammatory agents may have a role to play in treating ALS. COX-2 is a particularly attractive target because of its marked increase in ALS spinal cord...

..In the case of Alzheimer's disease, inflammatory processes thus have the potential for turning a relatively slowly progressing condition into one characterized by rapid neurodegeneration...

..The results varied from 0.13 years for the most rapidly progressing case to 7.98 years for the most slowly developing case. The average for 8 cases was 2.51 years...

..Therapeutic intervention in key inflammatory processes holds great promise for the amelioration of AD and possibly other neurodegenerative disorders...

..Microglial-vascular reciprocal interactions could serve a critical role in the amplification and perpetuation of inflammatory reactivity in AD brain...

..It is concluded that the stimulants activated multiple intracellular pathways, and that combination therapies inhibiting these pathways might be beneficial for treating neurodegenerative disorders...

..We investigated which stage of epileptogenesis is critical for eliciting progenitor cell division and whether seizure-induced neuronal degeneration is responsible for the enhancement of progenitor cell division...

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..Such increases have been observed in AD brains. We hypothesized that these increased levels of inflammatory mediators could lead to an increase in core body temperature in AD patients...

..5 microM respectively. We hypothesize that the neuroinflammation stimulated by release of an excess of normal alpha-synuclein or by release of its mutated forms can be involved in the pathobiology of PD...

..The H(2)S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant, and neuroprotective properties...

..On the other hand, the mood stabilizer and anti-manic agent lithium chloride has mixed effects on IFN-gamma-induced microglial activation...

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..These brain phenomena combined with epidemiological evidence of a protective effect of antiinflammatory agents suggest that such agents may have a role to play in treating the disease...

..Here we review recent advances in our understanding of one such disorder, Parkinson's disease, in which anti-inflammatory drugs are now becoming a new therapeutic focus...

..Whether such drugs will slow the process of Parkinson's disease or reduce the high risk of dementia in such patients remains to be determined in future work...

..Whether they would affect the more consolidated, cross-linked Abeta of AD and, if they did, whether that would really prove an effective treatment for the disease remains for future research to determine...

..H(2)S releasing drugs may have therapeutic potential in neurodegenerative disorders of aging such as Alzheimer disease and Parkinson disease...

..The upregulation appears greater than that found in inflamed arthritic joints. These data support the hypothesis that chronic inflammation may play an important role, if secondary, in the pathogenesis of PD...

..These data suggest that furin may be involved in producing the pathological fragment of ABriPP in vivo and that inhibition of furin might be a method of treating this disorder...

..There are some promising leads, but more definitive clinical trials are required. Any agent designed to slow progression should clearly be used at an early stage of the disorder; therefore methods of early diagnosis are also essential...

..The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically...

..The data suggest that inhibition of proinflammatory LT production by 5-LOX inhibition could selectively reduce toxicity of microglial cells and thus be beneficial in neuroinflammatory diseases...

..No breakthrough has yet occurred and present thinking is that combinations of drugs may be required to slow the multifactorial neurodegeneration process effectively...

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..The data suggest that certain protease inhibitors could inhibit microglial-mediated toxicity. They might represent a novel class of drugs with benefit in diseases where overactivity of microglia contributes to the pathogenesis...

..72%). Patients with RA appear to be relatively spared from AMD. We hypothesize that this results from long term antiinflammatory treatment. Genetic or environmental factors could also be responsible...

..If insults occur that repeatedly expose a region of MBP normally sheltered from immunosurveillance, a self-sustaining immune reaction might result...

..Mention will also be made of some recent work on animal models of possible relevance to AD and inflammation...

..Only residual plasma in vessels was stained with the antibody to fibronectin. Negative staining was obtained with antibodies to the fibronectin receptor VLA-5 and VLA-3. Trace staining was obtained with the antibody to VLA-2...

..In addition it was shown that stimulated astrocytes could also express complement C9 mRNA, though C9 protein was not detectable in culture supernatants...

..Overactive microglia secrete many toxic materials. Inhibition of microglial activation is another potential therapeutic target...

..The accumulation of thrombin and prothrombin in NFTs supports the hypothesis that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases...

..In particular, the mouse models of Alzheimer disease have also led to the development of new therapeutic strategies such as vaccination and modulation of microglial activity...

..In summary, LRRK2 is constitutively expressed in neurons and also in glial cells of human brain. It strongly associates with pathological inclusions in several neurodegenerative disorders...

..Stimulation is provided by a variety of inflammatory cytokines. Agents which reduce the intensity of inflammation should have broad spectrum application in degenerative diseases of aging...

..The results indicate that Lrrk2 is linked to frontotemporal atrophy of PPND type caused by N279K tau mutation. They also show that chronic inflammation is involved in the pathogenesis of N279K/FTDP-17/PPND...

..The chronicity of the degenerative disease, contrasted with the acuteness of the lesion, may explain the difference...

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..New therapeutic approaches to PD and the synucleinopathies may result from limiting the interaction between Lrrk2 and alpha-synuclein...

..The functions of the presenilins are not yet known, but available evidence points to pyramidal neurons as the most logical site for pathological change in AD...