Peripheral Biomarkers of Parkinson’s Disease Progression and Pioglitazone Effects

Simon, David K.; Simuni, Tanya; Elm, Jordan; Clark-Matott, Joanne; Graebner, Allison K.; Baker, Liana; Dunlop, Susan Rebecca; Emborg, Marina E.; Kamp, Cornelia; Morgan, John C.; Ross, G. Webster; Sharma, Saloni; Ravina, Bernard

doi:10.3233/jpd-150666

Cited by 29 publications

(13 citation statements)

References 34 publications

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“…Pioglitazone administration has been reported to increase PGC1α mRNA expression in the adipose tissue of diabetic patients [48,49], in the heart and pancreas of diabetic rats [47], and in skeletal muscle of diabetic mice [50] and to increase PGC1α protein expression in skeletal muscle of diabetic mice [50]. However, administration of pioglitazone to non-diabetic PD patients did not affect leukocyte PGC1α mRNA levels [51], and, in wild type mice, it induced either an increase [52] or decrease [53] in liver PGC1α mRNA levels. These findings, combined with our results, suggest that PGC1α may be a more reliable marker of PPARγ activation in diabetic patients and animal models of diabetes than in subjects without metabolic syndrome.…”

Section: Can Target Engagement Of Pparγ By Pioglitazone Be Detected Imentioning

confidence: 99%

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

et al. 2020

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Cardiac dysautonomia is a common nonmotor symptom of Parkinson's disease (PD) associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies for PD cardiac neurodegeneration are not available, and biomarkers of target engagement are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) recapitulates PD cardiac dysautonomia pathology. We recently used positron emission tomography (PET) to visualize and quantify cardiac sympathetic innervation, oxidative stress, and inflammation in adult male rhesus macaques (Macaca mulatta; n = 10) challenged with 6-OHDA (50mg/kg; i.v.). Twenty-four hours post-intoxication, the animals were blindly and randomly assigned to receive daily doses of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5mg/kg p.o.) or placebo (n = 5). Quantification of PET radioligand uptake showed increased oxidative stress and inflammation one week after 6-OHDA which resolved to baseline levels by twelve weeks, at which time pioglitazone-treated animals showed regionally preserved sympathetic innervation. Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and sex matched normal controls (n = 5). In the heart, 6-OHDA-treated animals showed a significant loss of sympathetic nerve fibers density (tyrosine hydroxylase (TH)-positive fibers). The anatomical distribution of markers of sympathetic innervation (TH) and inflammation (HLA-DR) significantly correlated with respective in vivo PET findings across left ventricle levels and regions. No changes were found in alpha-synuclein immunoreactivity. Additionally, CD36 protein expression was increased at the cardiomyocyte intercalated discs following PPARγ-activation compared to placebo and control groups. Systemic 6-OHDA decreased adrenal medulla expression of catecholamine producing enzymes (TH and aromatic L-amino acid

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Section: Can Target Engagement Of Pparγ By Pioglitazone Be Detected Imentioning

confidence: 99%

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

et al. 2020

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“…To this end, these findings have prompted translation of PPAR agonists, specifically pioglitazone, into a multi-center, double-blind phase 2 clinical trial [47]. This trial also attempted to find peripheral biomarkers for PD that included leukocyte PGC-1α, IL-6, and urine 8-hydroxydeoxyguanosine [48]. There were no changes in peripheral biomarkers observed.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease

Olson

Gendelman²

2016

Current Opinion in Pharmacology

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While immune control is associated with nigrostriatal neuroprotection for Parkinson’s disease, direct cause and effect relationships have not yet been realized, and modulating the immune system for therapeutic gain has been openly debated. Here, we review how innate and adaptive immunity affect disease pathobiology, and how each could be harnessed for treatment. The overarching idea is to employ immunopharmacologics as neuroprotective strategies for disease. The aim of the current work is to review disease-modifying treatments that are currently being developed as neuroprotective strategies for PD in experimental animal models and for human disease translation. The long-term goal of this research is to effectively harness the immune system to slow or prevent PD pathobiology.

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“…Surprisingly, a recent 44-week placebo-controlled phase 2 study in 210 PD patients did not show the neuroprotective effect of this drug [119]. In addition, a different study could not identify a reduction in the biomarkers of PD in patients on pioglitazone, such as leukocyte PGC-1α , plasma interleukin 6, and urine 8-hydroxydeoxyguanosine [120]. However, it is important to underline that these biomarkers are not FDA approved.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Relationship between Type II Diabetes Mellitus and Parkinson’s Disease: A Systematic Review

Maluf

Feder

Carvalho

2019

Parkinson's Disease

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In the early sixties, a discussion started regarding the association between Parkinson's disease (PD) and type II diabetes mellitus (T2DM). Today, this potential relationship is still a matter of debate. This review aims to analyze both diseases concerning causal relationships and treatments. A total of 104 articles were found, and studies on animal and “in vitro” models showed that T2DM causes neurological alterations that may be associated with PD, such as deregulation of the dopaminergic system, a decrease in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), an increase in the expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes 15 (PED/PEA-15), and neuroinflammation, as well as acceleration of the formation of alpha-synuclein amyloid fibrils. In addition, clinical studies described that Parkinson's symptoms were notably worse after the onset of T2DM, and seven deregulated genes were identified in the DNA of T2DM and PD patients. Regarding treatment, the action of antidiabetic drugs, especially incretin mimetic agents, seems to confer certain degree of neuroprotection to PD patients. In conclusion, the available evidence on the interaction between T2DM and PD justifies more robust clinical trials exploring this interaction especially the clinical management of patients with both conditions.

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Peripheral Biomarkers of Parkinson’s Disease Progression and Pioglitazone Effects

Cited by 29 publications

References 34 publications

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease

Analysis of the Relationship between Type II Diabetes Mellitus and Parkinson’s Disease: A Systematic Review

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