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Is Parkinson’s Caused By Inflammation

Adaptive Immunity: Activation Of Cell

Reducing Inflammation and Parkinson’s Disease

The adaptive immune system shows specific responses against foreign antigens activating different T or B lymphocytes . The surveillance of homeostasis in the CNS is guaranteed by naïve and memory T cells . T cell infiltration has been discovered in post-mortem brain sections of PD patients . The analysis of T cell subsets in peripheral blood mononuclear cells of affected patients showed altered immune responses and a decrease in the overall number of lymphocytes, but not in their frequency . What is more, PD presents a particular immunological profile unseen in other neurological diseases , where increased numbers of memory T cells and a reduced quantity of naïve T cells have been registered . As well, low CD4+:CD8+ ratio and a shift to more IFN- vs. IL-4-producing T cells have suggested the presence of cytotoxic T cell responses in PD patients .

The Analysis Of Clots Formed From Fibrinogen Incubated With Recombinant Gingipain R1

Confocal microscopy was used to visualize the clot structure of purified fibrin marked with Alexa 488, with and without exposure to recombinant gingipain R1 , and with and without exposure to P gingivalis LPS . Note that fibrinogen was pre-incubated with the inflammagens,

followed by clot formation with thrombin. is a representative purified fluorescent fibrin clot, showing a fibrin network with distinctive fibers. shows a representative fibrin clot after fluorescent fibrinogen was incubated with P. gingivalis LPS. Fibrin networks display a denser and more matted network. Purified fibrinogen was also exposed to two concentration of RgpA and 500 ng L1 . RgpA greatly inhibited fibrin formation synthesis in a concentration-dependent manner. A combination of both the LPS and RgpA was also added simultaneously to purified fibrinogen, and the resulting clot is shown in . Interestingly, this clot appeared similar to the clot where only LPS was added . Although the interactions between the various protease domains, and RgpA in particular, with LPS and their combined affects on fibrin is unknown, LPS is known to bind to domains of

Allergic Reaction Versus Parkinsons Disease

Allergic reaction is tied to the immune system. It responds when otherwise safe substances enter the body but are incorrectly identified as harmful foreign bodies. The immune systems job is to protect us from illness, including viruses, bacteria, infection and disease. When the immune system overreacts, a large amount of histamine is released in an attempt to protect our body from attack. Histamine is a key defender against foreign bodies that could cause us harm. It fights infection and disease but also causes inflammation, which creates many symptoms of allergy including shortness of breath, itchiness, swelling and hives.

Dopamine is a transmitter neuron that sends signals to other neurons that control pleasure, sensation and movement. Its found in large concentrations in the substantia nigra, in the brain. In Parkinsons Disease, dopamine response is very low. Motor function symptoms of Parkinsons tend to show up when 60-80 percent of the cells that produce dopamine are damaged or otherwise not producing sufficient levels dopamine. The main early symptoms of Parkinsons Disease include stiff muscles, slow movements, tremors and trouble with walking and balance. Non-motor symptoms of Parkinsons include congested nasal passages, difficulty swallowing or breathing, and dermatitis . Non-motor symptoms of Parkinsons and symptoms of allergy can be very similar.

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Brain Inflammation Link To Parkinsons Not New

The idea that brain inflammation is somehow involved in Parkinsons disease is not new, and previous studies have already linked it to non-motor symptoms like depression, fatigue and cognitive impairment.

Previous research also suggests that inflammation in the brain could drive cell death, and drugs that target this process could offer new treatments to slow progression of the disease. For instance, a study published as far back as 2007 suggested that brain cell death in parkinsons may be reduced by blocking enzyme activity.

However, Prof. Brundin explains that many of these previous studies looking at inflammatory markers in the cerebrospinal fluid of Parkinsons patients have involved only small numbers of patients, often without comparing them to healthy controls.

For their investigation, the team enrolled 87 Parkinsons patients between 2008 and 2012, together with 37 healthy controls.

All participants had routine blood tests and underwent physical exams.

The team tested for the following markers of inflammation: C-reactive protein , interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 and macrophage inflammatory protein 1-beta.

The results showed that increased levels of inflammatory markers were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire group of Parkinsons patients.

What Activates The Microglia

Inflammatory pathways in Parkinsons disease. An acute ...

A key issue for understanding the role of innate inflammation in the CNS in the pathogenesis of PD is to discover what are the stimuli that lead to the activation of microglia, in particular, those that drive them to a phenotype that promotes neurodegeneration. Neuronal degeneration per se will lead to the generation of numerous molecules that may activate myeloid cells and release the inhibitory tone on microglia as discussed above. In vitro studies have shown that neuromelanin and -synuclein aggregates lead to activation of the microglia and the generation of potentially neurotoxic molecules. However, the mismatch between in vitro and in vivo experimental approaches seems to have attracted little critical appraisal despite the fact that the same issues pertain in a number of other protein misfolding diseases. The response of a cell of the macrophage lineage is critically dependent not only on the concentration of the stimulus but also the rate of change of the stimulus, any prior stimulation, and the local microenvironment. It seems very unlikely that a microglia cell will respond in the same manner to the slow accumulation of -synuclein aggregates or slow progressive release of neuromelanin as it will to the sudden addition of these agents to a culture plate, a microenvironment in which the microglia have already been acutely removed from the tonic inhibition provided by ligands expressed on the surrounding neurons in vivo.

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Connection Between Inflammatory Stimulus And Parkinson’s Disease Examined

Date:
American Physiological Society
Summary:
The precise cause of Parkinsons Disease is unknown, but there is consensus that an inflammatory event or episode is involved in the initiation of neurodegeneration. A new study has brought the understanding of inflammations role a step further.

Parkinson’s disease is a progressive degenerative disease affecting a person’s ability to coordinate and control their muscle movement. What starts out as a tremor in a finger will eventually lead to difficulty in writing and speaking, and ultimately the inability to walk without assistance. Since the 1950s research has shown that people with Parkinson’s have decreased levels of the chemical dopamine in their brains, which is involved in sending messages to the part of the brain that controls coordination and movement. Subsequent research has found that dopamine-generating cells, known as dopaminergic neurons, are also absent in a specific area of the brain in those with PD.

Methodology

Twelve male Sprague-Dawley rats were treated with intravenous LPS in saline, 12 control rats were treated with saline, and all were maintained for up to 48 hours before euthanasia and brain removal. Brains were removed from both groups at defined times, blood and other tests were conducted, and images of various sections of the brain, including the olfactory bulb, cortex and cerebellum, were taken using fluorescent microscopy.

Results and Conclusions

As a result, the researchers suggest:

Next Steps

Thromboelastography Cholesterol And Hba1c Levels And Ultrasensitive Crp

HbA1c levels were significantly increased in the PD sample with a notably dysregulated lipid profile . TEG results point to the fact that PD WB is hypercoagulable. TEG analysis exhibited significant differences in five of the groups of the assessed parameters. The PD group presented a significant increase in the initial rate of clot formation . Significant elevation in alpha angle suggests more cross-linking of fibrin fibers, and time to maximum rate of thrombus generation was decreased. These results have significance to our RgpA results that we discuss later.

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Want To Learn More About The Latest Research In Parkinsons Disease Ask Your Questions In Our Research Forum

Researchers in China conducted a meta-analysis of published literature focusing on Parkinsons risk in IBD using two databases, PubMed and Embase, and including in their search the keywords ulcerative colitis and Crohns disease. For the meta-analysis, they included cohort or case-control studies with patients diagnosed with IBD, either ulcerative colitis and Crohns disease, and whose main outcome was Parkinsons.

Out of an initial pool of 172 studies, four studies accounting for a total of more than 8.9 million patients were included in the meta-analysis.

Performed in the United States, Denmark, Sweden and Taiwan, these four studies assessed the incidence rate of Parkinsons in IBD patients, specifically those with Crohns and ulcerative colitis. Three had been conducted in 2018, and one in 2016.

To our knowledge, this is the first MA to focus on the risk of PD in IBD patients, the research team wrote. Despite the small number of studies included, the patient numbers were large due to the population-based nature of the included studies.

Pooled results of all studies suggested that an IBD diagnosis was associated with a 41% increased risk of developing Parkinsons.

Among the IBD patients, the risk for Parkinsons was not affected by gender, with similar rates seen in male and female patients, or by age.

More comprehensive and detailed MA using a larger number of studies are required to validate our findings in the future, the study concluded.

Recombinant Gingipain R1 Protease And Alexa 488

Could inflammation be important to Parkinsons? Dr Sally Cowley

Purified fibrinogen with Alexa 488 was prepared to a final concentration of 2 mg.mL1. Clots were prepared by adding human thrombin as per the above protocol. Clots were also viewed with the confocal microscope and fluorescent fibrinogen was excited at 488 nm, with emission measured at 508 to 570 nm. As the gingipains antibody used above has the same excitation and emission as the purified fibrinogen, we could not trace the added gingipains with this antibody. We also incubated purified fluorescent fibrinogen with LPS from P. gingivalis with and without RgpA . Where we combined the LPS and the RgpA, both were added simultaneously followed by an incubation period of 30 min.

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Important Analyses And Stories Relevant With Age At Which Parkinsons Disease What Is Parkinsons Disease And Causes Explained By Drberg

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Dr. Berg talks about Parkinsons Disease, which involves substantia Nigra. This part of the brain controls dopamine. The symptoms involve stiffness, poor posture, resting tremor and dementia. There is a link between pesticide exposure and head trauma in these causes. There is also an abnormal protein that develops in the brain which interferes with dopamine. I recommend taking an enzyme called SERROPEPTASE take 2 three times a day on an empty stomach.

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Innate Immune Regulation By Grs In Microglia During Dopamine Neurodegeneration

Nigral dopamine neurodegeneration triggered by MPTP is significantly reduced by pharmacological treatments with GC agonists e.g., corticosterone that artificially increase GCs above endogenous levels, conversely adrenalectomy augments dopamine neuronal loss indicating that high levels of GCs present during MPTP intoxication protect dopamine neurons. Immuno-labeling of GR revealed its localization mainly in the nucleus of microglia and its quantification was carried out in substantia nigra and striatum in saline and MPTP injected mice. The results showed that number of microglia with nuclear GR augmented from 35% in resting state to 7080% 3 days after MPTP injections, which then declined to almost normal levels after 3 weeks. Measurement of endogenous corticosterone levels showed a three-fold rise 1 day after MPTP . Importantly, these results indicate that GR activation during endogenous rise in corticosterone levels is progressive concurring loss of dopamine neurons . However increasing GC levels by corticosterone treatment results in significant neuroprotection likely because GR activation in microglia is rapid enough to counteract the inflammatory response mounted by activated glia.

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Inflammatory Bowel Diseases And Parkinsons Disease

Issue title: Special Issue: The Gut-Brain Axis in Parkinsons Disease Revisited

Guest editors: Teus van Laar

Article type: Review Article

Authors: Brudek, Tomasza b *

Affiliations: Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark | Copenhagen Center for Translational Research, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

Correspondence: Correspondence to: Tomasz Brudek, Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, Nielsine Nielsens Vej 6B, building 11B, 2nd floor, DK-2400 Copenhagen NV, Denmark. Tel.: +45 38635600 E-mail: .

Keywords: Parkinsons disease, inflammatory bowel disease, Crohns disease, ulcerative colitis, enteric nervous system, brain-gut axis, gastrointestinal track inflammation, inflammation

DOI: 10.3233/JPD-191729

Journal: Journal of Parkinson’s Disease, vol. 9, no. s2, pp. S331-S344, 2019

Abstract

Platelet Activation In Parkinsons Disease And Why They Might Be Targets For Upregulated Circulating Cytokines

New study highlights links between inflammation ...

We seek to provide a possible explanation for the significant platelet activation that we observed by closely looking at our cytokine results, and particularly some of the most prominent dysregulated inflammatory markers. We focus here mainly on IL-1, IL-1 , IL-17A, and TNF-, and appraised literature that previously linked upregulation of these molecules to platelet activation. These cytokines are all known to act as ligands to platelet receptors, which cause outside-in and inside-out platelet signaling See for a simplified diagram of such pathways receptor binding, as well as signaling.

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Thromboelastography Of Whole Blood And 20

Clot kinetics/property analysis was completed by means of TEG , on both control and PD WB samples. 340 L of WB samples were placed in a disposable TEG cup to which 20 L of 0.2 mol/L CaCl2 was added. CaCl2 is necessary to reverse the effect of the sodium citrate anticoagulant in the collection tube and consequently initiate coagulation.

Stored PPP samples of PD and healthy controls participants were transferred from 80°C to 20°C 24 h preceding the multiplex analysis. The samples were then analyzed in duplicate by means of Invitrogens Inflammation 20-Plex Human ProcartaPlexTM Panel and read on the Bio-Plex® 200 system . 20 anti- and pro-inflammatory molecules were measured in a multiplex analysis and biomarkers measured included 4 anti-inflammatory molecules , and 16 pro-inflammatory molecules .

Antiinflammatory Therapies In Pd

While evidence strongly suggests that inflammation plays a major role in the etiology of a number of different forms of PD, emerging evidence also demonstrates that therapies used to lessen inflammation, including those directed against immune cells or inflammatory mediators, can play a positive role in halting the degeneration of DA neurons in several models of PD. Many studies suggest that inflammatory mediators such as TNF, PGE2, NO, free radicals, and other immune mediators play a role in the pathogenesis of PD and degeneration of dopamineproducing neurons, and that the use of specific reagents that target these mediators, inhibition of cellular signaling mechanisms that regulate the production of these mediators, or the use of neurotrophic factors that help protect against the neurotoxicity induced by these mediators hold significant promise as therapeutic treatments for PD. In addition, epidemiological and observational studies already suggest that use of antiinflammatory drugs lower the risk of developing PD .

LPS induced mice and mesencephalic culture

Therapy
  • Huang Y, Halliday GM. Aspects of innate immunity and Parkinson’s disease. Front Pharmacol. 2012 3:33.
  • 6. Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007 Mar 28:13845.
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    Pd Genes And Inflammatory Response

    Roughly 90% of PD cases exhibit a sporadic mode of incidence leaving approximately 10% attributed to genetic forms of the disease. Considerable effort has focused on rare monogenic causes of PD with particular emphasis on the role of alpha-synuclein, LRRK2, Parkin, DJ-1, and PINK1 in inflammatory response with the hope that understanding the underlying disease-causing mechanisms would shed light on all forms of the disease. Mutation of Parkin, DJ-1, and PINK1 has been reported to give rise to autosomal recessive forms of PD by modulating neuroinflammation. PD has been associated with dysfunctional mitochondria, impaired autophagy, oxidative stress, and dysfunctional protein homeostasis. Parkin, DJ-1, and PINK1 are thought to exhibit neuroprotective properties by lessening oxidative stress, enhancing mitochondrial function, and mediating protein homeostasis. It should be noted that genetic forms of PD may have some phenotypic differences from idiopathic PD.

    Confocal Analysis Of Plasma Clots

    The Chronic Disorders are Caused Chronic Inflammation

    Confocal analysis, as well as raw data of the clot analysis are shown in the and in . Control and PD platelet poor plasma clots, with markers illuminate amyloid fibrin protein structure were imaged on a confocal microscope. Control clots display disperse signal. PD samples contain significantly greater amyloid-specific signal than control donors in all three channels: blue , red , and green .

    Examples of clots created with platelet poor plasma for a representative control and two representative PD individuals to show amyloid fibrin protein structure. Three fluorescent markers that bind amyloid protein were used, Amytracker 480, 680, and ThT .

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