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Neuroinflammation – Part 2

March 16, 2011

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Activated microglia. Alpha-synuclein aggregation. Neuronal loss in the SN. Long term persistence of effect. There is at least one other known trigger for a near identical innate immune response.  That is the effect of fetal exposure to the endotoxin lipopolysaccharide (LPS) as shown in the following reports:
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1: Exp Neurol. 2006 Jun;199(2):499-512. Epub 2006 Feb 28.
Progressive dopamine neuron loss following supra-nigral lipopolysaccharide (LPS) infusion into rats exposed to LPS prenatally.
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Ling Z, Zhu Y, Tong C, Snyder JA, Lipton JW, Carvey PM.
Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612,
USA.
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Toxin-induced animal models of Parkinson’s disease (PD) exhibit many of the same neuroinflammatory changes seen in patients suggesting a role for inflammation in DA neuron loss. Yet, despite this inflammation, the progressive loss of DA neurons that characterizes PD is rarely seen in animals. We infused lipopolysaccharide (LPS) or saline into 7-month-old rats that had been exposed to LPS or saline prenatally and assessed them for DA neuron loss and inflammatory measures (interleukin 1 beta, tumor necrosis factor-alpha, glutathione, and activated microglia) over a period of 84 days to examine the role of pre-existing inflammation in progressive DA neuron loss. LPS infusion into both prenatal treatment groups produced neuroinflammation during the 14 days of LPS infusion that subsequently reverted toward normal over the next 70 days. In animals with pre-existing inflammation (i.e., prenatal LPS), however, the acute changes seen were attenuated, but took much longer to return to normal suggesting a prolonged inflammatory response. These inflammatory changes were consistent with the greater acute DA neuron loss seen in the prenatal saline controls and the progressive DA neuron loss seen only in the animals exposed to LPS prenatally. Interestingly, both prenatal treatment groups exhibited increases in microglia over the entire 84-day course of the study. These data  suggest that pre-existing neuroinflammation prolongs the inflammatory response  that occurs with a second toxic exposure, which may be responsible for progressive DA neuron loss. This provides further support for the multiple hit”  hypothesis of PD.

PMID: 16504177 [PubMed – indexed for MEDLINE]
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1: Glia. 2007 Apr 1;55(5):453-62.
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.
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Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT.
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Bowles Center for Alcohol Studies, School of Medicine, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson’s disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral  TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver).  Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further,  LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson’s disease. (c) 2007 Wiley-Liss, Inc.
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PMID: 17203472 [PubMed – indexed for MEDLINE]

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We thus far have three distinct paths with a common endpoint in the microglial generated inflammatory state. One path (Senior Onset) originates with a virus and travels  along the nervous system’s pathways leaving a trail of Lewy bodies behind. The second (Young Onset) is already present at birth as a result of fetal encounter with lipopolysaccharide (LPS) and progresses at a rate determined in part by encounters with environmental factors. The latter form also is influenced by alterations in the fetal  endocrine system, particularly the HPA Axis – the heart of the stress circuit. And the third (Adult Onset) originates with adult LPS exposure. Regardless of the path, however, neuroinflammation is the driving force. Before we explore either path, it would behoove us to become familiar with the common elements.

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From http://www.bcmj.org/inflammation-pathogenesis-parkinson-s-disease
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Inflammation in the pathogenesis of Parkinson’s disease
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Edith McGeer, PhD & Koji Yasojima, MD & Patrick L. McGeer, MD
BCMJ, Vol. 43, No. 3, April 2001, page(s)
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ABSTRACT:
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The immunohistochemical demonstration of reactive microglia and activated complement components suggests that chronic inflammation occurs in affected brain regions in both Parkinson’s disease and Alzheimer’s disease. Chronic inflammation can damage host cells, and there is epidemiological evidence that it contributes to the progressive neuronal loss in Alzheimer’s disease. Reports in the literature indicate that anti-inflammatory agents inhibit dopaminergic cell death in animal models of Parkinson’s disease. There is a marked elevation in the levels of the messenger ribonucleic acids for complement proteins and markers of activated microglia in affected regions in both Parkinson’s disease and Alzheimer’s disease. The upregulation appears greater than that found in inflamed arthritic joints. These data support the hypothesis that chronic inflammation may play an important, if secondary, role in the pathogenesis of Parkinson’s disease.
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Introduction
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Classical dogma taught that the brain is immunologically privileged and does not mount an endogenous immune response. Immunohistochemical and molecular biological evidence accumulated over the past decade, however, has shown that the brain is capable of sustaining an immune response and that the result may be damaging to host cells. The brain, rather than being immunologically privileged, may be particularly vulnerable since neurons are postmitotic. They cannot divide so that, once lost, they are not replaced. The evidence for a chronic inflammatory reaction in the brain is particularly strong in Alzheimer’s disease (AD), where it has been extensively studied,[1,2] but there is also evidence suggesting that a local immune reaction occurs in affected regions of the brain in Parkinson’s disease (PD).[3] The inflammation is silent because the brain has no pain fibres. Moreover, the local immune reaction does not involve the peripheral immune system. It occurs without antibodies and without significant involvement of T cells. Instead, the reaction depends upon the synthesis of inflammatory components by local neurons and glia, and especially resident phagocytes-which, in the brain, are the microglia. The complement system, microglia, and inflammatory cytokines appear to play key roles.
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The complement system
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The complement is a phylogenetically primitive system, considerably predating the adaptive immune system, which developed in later vertebrates. It is thus not surprising that the system can be activated by molecules other than antibodies. One such molecule, which is found elevated in the substantia nigra in PD, is C-reactive protein. Once activated, the complement cascade Figure 1 produces anaphylatoxins that promote further inflammation, opsonizing components that mark material for phagocytosis and the membrane attack complex, which is directly lytic to cells. The membrane attack complex inserts itself into viable cell membranes, causing them to leak and produce cell death. It is intended to destroy foreign cells and viruses, but host cells are at significant risk of bystander lysis.
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The presence of complement proteins, including all components of the membrane attack complex, has been shown intracellularly on Lewy bodies and on oligodendroglia in the substantia nigra in PD [4,5] and familial PD.[6] Such oligodendroglia have been described as complement activated oligodendroglia. Staining for all the complement components is either absent or very weak in control substantia nigra.[4,5]
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Microglia
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Microglia constitute about 10% of all glia. They are generally in the resting state in the normal adult brain. When activated, they upregulate or newly express a variety of receptors and other molecules involved in inflammation and phagocytosis. In the activated state, they also produce large amounts of superoxide anions and other potential neurotoxins. In culture, microglia have been shown to contribute to neurotoxicity, including that of dopaminergic cells.[7] A profusion of reactive microglia is seen in the substantia nigra and striatum, not only in idiopathic PD, [5,8] but also in familial PD, [6] as well as in the parkinsonism-dementia complex of Guam (EGM et al, unpublished data, 2001). The presence of many activated microglia in the substantia nigra of humans dying years after exposure to the toxin MPTP testifies to the fact that once the fire of inflammation is lit, it continues to burn long after the initiating event.[9]
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Reactive microglia are also seen in the basal ganglia in 6-hydroxydopamine and MPTP animal models of PD, and there are several reports that anti-inflammatories inhibit dopaminergic neurotoxicity in such animal models.[3]
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Microglia can be activated by products of the classical complement cascade, by various inflammatory cytokines, and by chromogranin A,[10,11] which has been reported to occur in PD substantia nigra.[12]
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Cytokines
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Inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6, amplify and sustain inflammation and immune responses. In the periphery, they are thought to be primarily responsible for many of the clinical and pathological manifestations of such diseases as rheumatoid arthritis and inflammatory bowel syndrome. It is of some interest, therefore, that increased levels of interleukin-1ß, interleukin-6, and tumor necrosis factor-alpha have been found in the basal ganglia and CSF of PD patients.[3] The increase in tumor necrosis factor-alpha was particularly dramatic, being 366% in tissue and 432% in CSF.[13] Moreover, the presence of glial cells immunoreactive for tumor necrosis factor-alpha and/or interleukin-1ß has been reported in the substantia nigra of PD patients.[14,15]
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Intensity of the inflammatory reaction
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The large increase in levels of the inflammatory cytokines and the profusion of reactive microlgia seen in the substantia nigra in PD suggests an intense inflammatory reaction. In order to gain a better understanding of the intensity of the reaction, the levels of the messenger ribonucleic acids for key inflammatory proteins in the brains of PD cases can be compared with controls. Preliminary results are shown in Figure 2.[16] The messenger ribonucleic acids for all components of the classical complement pathway are markedly elevated in the parkinsonian substantia nigra and caudate, but not in areas outside the basal ganglia. This is illustrated for C1q and C9, the initial and final components, in Figure 2A. Figure 2B illustrates that the same holds true for HLA-DR, a marker of activated microglia, and for C-reactive protein, an acute phase molecule capable of activating the complement cascade. Figure 2C compares the elevations of these messenger ribonucleic acids in PD substantia nigra to those in AD hippocampus and in an arthritic joint removed surgically because of intractable pain. The inflammatory reaction in affected brain regions in these neurodegenerative diseases seems to be, at least by this measure, more intense than that in arthritic joints.
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Conclusions
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The evidence that a chronic inflammatory reaction may be contributing to neuronal death is certainly not as strong in PD as it is in AD, where there are epidemiological data [17] and one small pilot trial [18] to support the hypothesis that anti-inflammatory agents might delay the onset and slow the progression of the disease. Nevertheless, it seems possible that treatment with anti-inflammatory agents might slow the progress of dopaminergic cell death in PD. Anti-inflammatory treatment of PD cases might also serve to inhibit the onset of dementia, a condition to which those with parkinsonism seem to be more prone than the general population. Postmortem examination of the cortex and hippocampus of PD patients with dementia reveals the same type of inflammatory changes seen in those regions in persons dying with primary AD (EGM et al, unpublished data, 2001). The human and economic benefits would be significant.
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One question that immediately comes to mind is just how prevalent inflammation is among PWP? As noted below, it seems to be universal.
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1: Br J Pharmacol. 2007 Apr;150(8):963-76. Epub 2007 Mar 5.
Inflammation as a causative factor in the aetiology of Parkinson’s disease.
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Whitton PS.
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1Department of Pharmacology, The School of Pharmacy, London, UK.
peter.whitton@pharmacy.ac.uk
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting mainly the elderly, although a small proportion of PD patients develop the illness at a much younger age. In the former group, idiopathic PD patients, the causes of the illness have been the subject of longstanding debate with environmental toxins, mitochondrial dysfunction, abnormal protein handling and oxidative stress being suggested. One problem has been that the epidemiology of PD has offered few clues to provide evidence for a single major causative factor. Comparatively recently it has been found that in both patients and experimental models of PD in animals neuroinflammation appears to be a ubiquitous finding. These cases present with all of the classical features of inflammation including phagocyte activation, increased synthesis and release of proinflammatory cytokines and complement activation. Although this process is vital for normal function and protection in both the CNS, as in the periphery, it is postulated that in the aetiology of PD this process may spiral out of control with over activation of microglia, over production of cytokines and other proinflammatory mediators as well as the release of destructive molecules such as reactive oxygen species. Given that dopaminergic neurons in the substantia nigra are relatively vulnerable to ‘stress’ and the region has a large population of microglia in comparison to other CNS structures, these events may easily trigger neurodegeneration. These factors are examined in this review along with a consideration of the possible use of anti-inflammatory drugs in PD.
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PMCID: PMC2013918
PMID: 17339843 [PubMed – indexed for MEDLINE]
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To summarize to this point:

 Inflammation of the CNS is universal among PWP. (Whitton 2007)

 That inflammation can be incredibly destructive and the substantia nigra is particularly vulnerable. (Various)

 At least three paths lead to the inflammatory state. I have labeled them Senior, Adult, and Young Onset.

 Senior is as described by Smeyne, Braak, et al and is initiated by the entry of a pathogen, presumably a virus, though the olfactory and gastric routes into the brain. This triggers the inflammatory immune response which persists long after the pathogen has disappeared. An assumed latency period of twenty years or more would make this population “bunch up” at the elder end of the distribution and account for the “standard” presentation.

 Adult arises from systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS). This could be triggered by either an unusual sensitivity or a particularly egregious exposure. The literature contains a striking example of this in the case history of Ines Niehaus, a young lab tech accidentally exposed to salmonella LPS who developed PD and whose report is available online. Seemingly the latency on this form is highly variable.

 Young onset has a more convoluted etiology and arises from prenatal exposure to the same endotoxin during critical time periods in the development of fetal structures. This form impacts not only the nervous and immune systems, but also the endocrine, particularly the hypothalamus-pituitary-adrenal axis, as shown by Carvey and others. The effect seems to manifest post-puberty. Assuming a 20-year progression to symptoms, this would result in cases becoming evident abou the age of forty. This group is highly influenced by “environmental insult” due to synergistic forces with the LPS.

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