scholarly journals Do PPAR-Gamma Agonists Have a Future in Parkinson's Disease Therapy?

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Anna R. Carta ◽  
Augusta Pisanu ◽  
Ezio Carboni
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ppar Gamma ◽  
Pathological Process ◽  
Immunomodulatory Activity ◽  
Peroxisome Proliferator ◽  
Immune Functions ◽  
Reactive Microglia ◽  
Peroxisome Proliferator Activated Receptor ◽  
Immune Mediated

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor (PPAR)-γagonists commonly used as insulin-sensitizing drugs for the treatment of type 2 diabetes. In the last decade, PPAR-γagonists have received increasing attention for their neuroprotective properties displayed in a variety of neurodegenerative diseases, including Parkinson's disease (PD), likely related to the anti-infammatory activity of these compounds. Recent studies indicate that neuroinflammation, specifically reactive microglia, plays important roles in PD pathogenesis. Moreover, after the discovery of infiltrating activated Limphocytes in the substantia nigra (SN) of PD patients, most recent research supports a role of immune-mediated mechanisms in the pathological process leading to chronic neuroinflammation and dopaminergic degeneration. PPAR-γare highly expressed in cells of both central and peripheral immune systems, playing a pivotal role in microglial activation as well as in monocytes and T cells differentiation, in which they act as key regulators of immune responses. Here, we review preclinical evidences of PPAR-γ-induced neuroprotection in experimental PD models and highlight relative anti-inflammatory mechanisms involving either central or peripheral immunomodulatory activity. Specific targeting of immune functions contributing to neuroinflammation either directly (central) or indirectly (peripheral) may represent a novel therapeutic approach for disease modifying therapies in PD.

scholarly journals Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-αAgonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Dedeepya Uppalapati ◽  
Nihar R. Das ◽  
Rahul P. Gangwal ◽  
Mangesh V. Damre ◽  
Abhay T. Sangamwar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Pbpk Modeling ◽  
Pharmacokinetic Parameters ◽  
Peroxisome Proliferator ◽  
Fenofibric Acid ◽  
Peroxisome Proliferator Activated Receptor

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR-αagonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 µg/1 µL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100 mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF-α, and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR-αagonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment.

The effect of preventive exercise on the neuroprotection in 6-hydroxydopamine-lesioned rat brain

2019 ◽  
Vol 44 (12) ◽  
pp. 1267-1275 ◽  
Author(s):  
Zeinab Rezaee ◽  
Sayed Mohammad Marandi ◽  
Hojjatallah Alaei ◽  
Fahimeh Esfarjani
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Treadmill Running ◽  
Spatial Learning And Memory ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
6 Hydroxydopamine

Parkinson’s disease is characterized by neurodegeneration and learning deficiency. Physical exercise can alleviate these symptoms by increasing the expression of some effective and relevant factors. The preventive effect of 16-week treadmill running in a rat model of Parkinson’s disease, before 6-hydroxydopamine (6-OHDA) induction, was assessed. Experimental groups consisted of sedentary (SED), SED+6-OHDA, exercised (EX), and EX+6-OHDA rats. Forty-eight hours after the last session of exercise, 6-OHDA was injected into the medial forebrain bundle (MFB). One week after the injection, behavioral tests, including spatial learning and memory, were assessed through Morris water maze (MWM) and apomorphine-induced rotation. Three weeks after the injection, mRNA expression and protein levels of the transcriptional co-activator peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5), brain-derived neurotrophic factor (BDNF), and tyrosine hydroxylase (TH) were measured in the striatum and the hippocampus of rats by applying real-time PCR and Western blotting. The findings indicate that exposure to 6-OHDA leads to impairments in behavioral and molecular functions. Exercise training prevents and reduces the symptoms caused by dopamine toxins. The results suggest that treadmill running can exert neuroprotective and have preventive effects to reduce Parkinson’s disease symptoms. Novelty Parkinson’s disease impairs spatial learning and memory. Parkinson’s disease reduced levels of PGC-1α, FNDC5, and BDNF and increased neurodegeneration in the striatum and the hippocampus. Treadmill running before disease attenuated 6-OHDA-induced memory deficit and elevated neuroprotection. Exercise has multiple effects on memory and biochemical factors.

Combination of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist and PPAR Gamma Co-Activator 1α (PGC-1α) Activator Ameliorates Cognitive Deficits, Oxidative Stress, and Inflammation in Rodent Model of Parkinson's Disease

2021 ◽  
Vol 19 ◽  
Author(s):  
Nihar Ranjan Das ◽  
Bhupesh Vaidya ◽  
Pragyanshu Khare ◽  
Mahendra Bishnoi ◽  
Shyam Sunder Sharma
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Lipoic Acid ◽  
Mitochondrial Biogenesis ◽  
Cognitive Deficits ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Alpha Lipoic Acid ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Background: PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson’s disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. Objective: In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Results: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. Conclusion: Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.

scholarly journals PGC-1s in the Spotlight with Parkinson’s Disease

2021 ◽  
Vol 22 (7) ◽  
pp. 3487
Author(s):  
Elena Piccinin ◽  
Anna Maria Sardanelli ◽  
Peter Seibel ◽  
Antonio Moschetta ◽  
Tiziana Cocco ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Dysfunctions ◽  
Process Failure ◽  
Cellular Pathways ◽  
Pathogenic Process

Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.

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

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Fauze Camargo Maluf ◽  
David Feder ◽  
Alzira Alves de Siqueira Carvalho
Keyword(s):  
Diabetes Mellitus ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Type Ii Diabetes ◽  
Type Ii Diabetes Mellitus ◽  
Alpha Synuclein ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor

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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