scholarly journals Iron Dysregulation and Inflammagens Related to Oral and Gut Health Are Central to the Development of Parkinson’s Disease

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 30
Author(s):  
Marthinus Janse van Vuuren ◽  
Theodore Albertus Nell ◽  
Jonathan Ambrose Carr ◽  
Douglas B. Kell ◽  
Etheresia Pretorius
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Systemic Inflammation ◽  
Cell Damage ◽  
Vascular Dysfunction ◽  
Iron Chelation ◽  
Gut Health ◽  
Novel Treatments ◽  
Randomized Controlled Clinical Trials ◽  
Iron Dysregulation

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

scholarly journals Bacteria, Lipopolysaccharides, Amyloid and the Role of Iron Dysregulation in Parkinson’s Disease

2020 ◽  
Author(s):  
Marthinus Janse van Vuuren ◽  
Theodore Albertus Nell ◽  
Jonathan Ambrose Carr ◽  
Douglas B Kell ◽  
Etheresia Pretorius
Keyword(s):  
Systemic Inflammation ◽  
Cell Damage ◽  
Vascular Dysfunction ◽  
Alpha Synuclein ◽  
Motor Deficits ◽  
Novel Treatments ◽  
Randomized Controlled Clinical Trials ◽  
Iron Dysregulation ◽  
Neuro Inflammation ◽  
Underlying Mechanisms

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuro-inflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby lipopolysaccharides may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments which may relieve the characteristic non-motor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

Platelet Behavior Contributes to Neuropathologies: A Focus on Alzheimer's and Parkinson's Disease

2021 ◽  
Author(s):  
Martin J. Page ◽  
Etheresia Pretorius
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vascular Dysfunction ◽  
Surface Receptors ◽  
Initiation Factors ◽  
Physiological Processes ◽  
Vascular Regulation ◽  
Inflammatory Mechanism ◽  
Neuro Inflammation ◽  
Neurovascular Dysfunction

AbstractThe functions of platelets are broad. Platelets function in hemostasis and thrombosis, inflammation and immune responses, vascular regulation, and host defense against invading pathogens, among others. These actions are achieved through the release of a wide set of coagulative, vascular, inflammatory, and other factors as well as diverse cell surface receptors involved in the same activities. As active participants in these physiological processes, platelets become involved in signaling pathways and pathological reactions that contribute to diseases that are defined by inflammation (including by pathogen-derived stimuli), vascular dysfunction, and coagulation. These diseases include Alzheimer's and Parkinson's disease, the two most common neurodegenerative diseases. Despite their unique pathological and clinical features, significant shared pathological processes exist between these two conditions, particularly relating to a central inflammatory mechanism involving both neuroinflammation and inflammation in the systemic environment, but also neurovascular dysfunction and coagulopathy, processes which also share initiation factors and receptors. This triad of dysfunction—(neuro)inflammation, neurovascular dysfunction, and hypercoagulation—illustrates the important roles platelets play in neuropathology. Although some mechanisms are understudied in Alzheimer's and Parkinson's disease, a strong case can be made for the relevance of platelets in neurodegeneration-related processes.

Role of iron and iron chelation in dopaminergic-induced neurodegeneration: Implication for Parkinson's disease

1992 ◽  
Vol 32 (S1) ◽  
pp. S105-S110 ◽  
Author(s):  
D. Ben-Shachar ◽  
G. Eshel ◽  
P. Riederer ◽  
M. B. H. Youdim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Iron Chelation

scholarly journals The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary—Ironing out the Brain

2019 ◽  
Vol 12 (3) ◽  
pp. 138 ◽  
Author(s):  
Robert R. Crichton ◽  
Roberta J. Ward ◽  
Robert C. Hider
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Iron Chelation ◽  
Brain Regions ◽  
Beta Thalassemia ◽  
Excess Iron ◽  
New Class ◽  
Clinical Conditions ◽  
The Brain

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong life. More recently, the use of deferiprone to chelate iron from various brain regions in Parkinson’s Disease and Friederich’s Ataxia has yielded encouraging results, although the side effects, in <2% of Parkinson’s Disease(PD) patients, have limited its long-term use. A new class of hydroxpyridinones has recently been synthesised, which showed no adverse effects in preliminary trials. A vital question remaining is whether inflammation may influence chelation efficacy, with a recent study suggesting that high levels of inflammation may diminish the ability of the chelator to bind the excess iron.

scholarly journals Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Perla Ugalde-Muñiz ◽  
Ingrid Fetter-Pruneda ◽  
Luz Navarro ◽  
Esperanza García ◽  
Anahí Chavarría
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Viability ◽  
Systemic Inflammation ◽  
Disease Model ◽  
Adequate Model ◽  
Mao B ◽  
Mptp Administration ◽  
Inflammatory Profile ◽  
The Impact

Systemic inflammation is a crucial factor for microglial activation and neuroinflammation in neurodegeneration. This work is aimed at assessing whether previous exposure to systemic inflammation potentiates neurotoxic damage by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and how chronic systemic inflammation participates in the physiopathological mechanisms of Parkinson’s disease. Two different models of systemic inflammation were employed to explore this hypothesis: a single administration of lipopolysaccharide (sLPS; 5 mg/kg) and chronic exposure to low doses (mLPS; 100 μg/kg twice a week for three months). After three months, both groups were challenged with MPTP. With the sLPS administration, Iba1 staining increased in the striatum and substantia nigra, and the cell viability lowered in the striatum of these mice. mLPS alone had more impact on the proinflammatory profile of the brain, steadily increasing TNFα levels, activating microglia, reducing BDNF, cell viability, and dopamine levels, leading to a damage profile similar to the MPTP model per se. Interestingly, mLPS increased MAO-B activity possibly conferring susceptibility to MPTP damage. mLPS, along with MPTP administration, exacerbated the neurotoxic effect. This effect seemed to be coordinated by microglia since minocycline administration prevented brain TNFα increase. Coadministration of sLPS with MPTP only facilitated damage induced by MPTP without significant change in the inflammatory profile. These results indicate that chronic systemic inflammation increased susceptibility to MPTP toxic effect and is an adequate model for studying the impact of systemic inflammation in Parkinson’s disease.

scholarly journals Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Antonio Martin-Bastida ◽  
Roberta J. Ward ◽  
Rexford Newbould ◽  
Paola Piccini ◽  
David Sharp ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trial ◽  
Parkinson's Disease ◽  
Iron Chelation ◽  
Controlled Clinical Trial ◽  
Phase 2 ◽  
Brain Iron ◽  
Double Blinded

TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson’s disease

2020 ◽  
Vol 29 (8) ◽  
pp. 1239-1252 ◽  
Author(s):  
Ting-Ting Wu ◽  
Te Liu ◽  
Xuan Li ◽  
Ya-Jing Chen ◽  
Tian-Jiao Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitor ◽  
Cell Damage ◽  
Epigenetic Modification ◽  
Substantia Nigra Pars Compacta ◽  
Epigenetic Therapy ◽  
Motor Deficits ◽  
Dna Hydroxymethylation

Abstract It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson’s disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.

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