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 PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

Activation of peroxisome proliferator-activated receptor–γ by a 12/15-lipoxygenase product of arachidonic acid: a possible neuroprotective effect in the brain after experimental intracerebral hemorrhage

2017 ◽  
Vol 127 (3) ◽  
pp. 522-531 ◽  
Author(s):  
Ruobing Xu ◽  
Shu Wang ◽  
Weishan Li ◽  
Zhen Liu ◽  
Jiaxin Tang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intracerebral Hemorrhage ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Peroxisome Proliferator ◽  
Double Labeling ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Autologous Whole Blood ◽  
The Brain ◽  
And Oxidative Stress

OBJECTIVEIn this study, the authors investigated the involvement of 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in the regulation of peroxisome proliferator-activated receptor–γ (PPARγ) after intracerebral hemorrhage (ICH) and its effects on hemorrhage-induced inflammatory response and oxidative stress in an experimental rodent model.METHODSTo simulate ICH in a rat model, the authors injected autologous whole blood into the right striatum of male Sprague-Dawley rats. The distribution and expression of 12/15-lipoxygenase (12/15-LOX) were determined by immunohistochemistry and Western blot analysis, respectively. Immunofluorescent double labeling was used to study the cellular localization of 12/15-LOX, and 15(S)-HETE was measured with a 15(S)-HETE enzyme immunoassay kit. Neurological deficits in the animals were assessed through behavioral testing, and apoptotic cell death was determined with terminal deoxynucleotidyl transferase–mediated biotinylated dUTP nick-end labeling.RESULTSRats with ICH had increased expression of 12/15-LOX predominantly in neurons and also in oligodendrocytes, astrocytes, and microglia. Moreover, ICH elevated production of 15(S)-HETE in the brain area ipsilateral to the blood injection. The PPARγ agonist, exogenous 15(S)-HETE, significantly increased PPARγ protein levels and increased PPARγ-regulated gene (i.e., catalase) expression in the ICH rats. Reduced expression of the gene for the proinflammatory protein nuclear factor κB coincided with decreased neuron damage and improved functional recovery from ICH. A PPARγ antagonist, GW9662, reversed the effects of exogenous 15(S)-HETE on the PPARγ-regulated genes.CONCLUSIONSThe induction of 15(S)-HETE during simulated ICH suggests generation of endogenous signals of neuroprotection. The effects of exogenous 15(S)-HETE on brain hemorrhage–induced inflammatory responses and oxidative stress might be mediated via PPARγ.

Abstract P224: Endothelin-1 Overexpression Preserves Endothelial Function in Mice with Vascular Smooth Muscle Cell-specific Deletion of PPAR-gamma

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sofiane Ouerd ◽  
Noureddine Idris-Khodja ◽  
Michelle Trindade ◽  
Jordan Gornitsky ◽  
Asia Rehman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Endothelial Function ◽  
T Regulatory Cells ◽  
Ppar Gamma ◽  
Reduce Blood Pressure ◽  
Vascular Damage ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Objective: Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure (BP) and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) using a tamoxifen inducible Cre-Lox system enhanced angiotensin II-induced vascular damage. Transgenic mice overexpressing endothelin (ET)-1 in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar gene in VSMC (sm Pparγ -/- ) would exaggerate ET-1-induced vascular damage. Methods and Results: Eleven-week-old male control, eET-1, sm Pparγ -/- and eET-1/sm Pparγ -/- mice were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and sacrificed 4 weeks later. Systolic BP determined by telemetry was higher in eET-1 (123±5 vs 109±2 mm Hg, P <0.05) and unaffected by sm Pparγ inactivation. Mesenteric artery (MA) vasorelaxation to acetylcholine was impaired only in sm Pparγ -/- (E max : 52.0±6.7 vs 82.2±4.9%, P <0.05). MA reactive oxygen species levels were increased 1.7±0.3-fold in sm Pparγ -/- ( P <0.05) and further increased in eET-1/sm Pparγ -/- (2.5±0.3-fold, P <0.05). MA perivascular fat monocyte/macrophage infiltration was higher in eET-1 and sm Pparγ -/- (331±34 and 326±49 vs 140±8 cells/mm 2 , P <0.05), and further increased in eET-1/sm Pparγ -/- (557±77, P <0.05). The spleen fraction of CD11b + cells was increased in sm Pparγ -/- (1.1±0.1 vs 0.47±0.1%, P <0.05) and further increased in eET-1/sm Pparγ -/- (1.8±0.2%, P <0.05). The spleen fraction of Ly-6C hi monocytes was increased in eET-1 and sm Pparγ -/- (24±3 and 27±4 vs 14±1%, P <0.05) but not in eET-1/sm Pparγ -/- . The spleen fraction of T regulatory cells was increased in sm Pparγ -/- (13±2 vs 9±1%, P <0.05) and decreased in eET-1 (7±1%, P <0.05), which was further decreased by eET-1/sm Pparγ -/- (3±1%, P <0.05). Conclusions: These results suggest that increased ET-1 paradoxically preserves endothelial function in mice with inactivated VSMC Pparγ despite enhanced oxidative stress. Flow cytometry data indicate that infiltrating monocyte/macrophages in these mice might be anti-inflammatory.

scholarly journals Rhein Relieves Oxidative Stress in an Aβ1-42 Oligomer-Burdened Neuron Model by Activating the SIRT1/PGC-1α-Regulated Mitochondrial Biogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhihui Yin ◽  
Xinyue Geng ◽  
Zhengyi Zhang ◽  
Ying Wang ◽  
Xiaoyan Gao
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Biogenesis ◽  
Antioxidant Defense System ◽  
Sirtuin 1 ◽  
Early Event ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Oxidative Stress ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 1

Neuronal mitochondrial oxidative stress induced by β-amyloid (Aβ) is an early event of Alzheimer’s disease (AD). Emerging evidence has shown that antioxidant therapy represents a promising therapeutic strategy for the treatment of AD. In this study, we investigated the antioxidant activity of rhein against Aβ1-42 oligomer-induced mitochondrial oxidative stress in primary neurons and proposed a potential antioxidant pathway involved. The results suggested that rhein significantly reduced reactive oxygen species (ROS) level, reversed the depletion of mitochondrial membrane potential, and protected neurons from oxidative stress-associated apoptosis. Moreover, further study indicated that rhein activated mitochondrial biogenesis accompanied by increased cytochrome C oxidase (CytOx) and superoxide dismutase (SOD) activities. CytOx on the respiratory chain inhibited the production of ROS from electron leakage and SOD helped to eliminate excess ROS. Finally, western blot analysis confirmed that rhein remarkedly increased the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) together with its upstream deacetylase sirtuin 1 (SIRT1), and activated downstream transcription factor nuclear respiratory factor 1, promoting mitochondrial biogenesis. In conclusion, our results demonstrate that rhein activates mitochondrial biogenesis regulated by the SIRT1/PGC-1α pathway as an antioxidant defense system against Aβ1-42 oligomer-induced oxidative stress. These findings broaden our knowledge of improving mitochondrial biogenesis as an approach for relieving neuronal oxidative stress in AD.

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.

Muscle immobilization and remobilization downregulates PGC-1α signaling and the mitochondrial biogenesis pathway

2013 ◽  
Vol 115 (11) ◽  
pp. 1618-1625 ◽  
Author(s):  
Chounghun Kang ◽  
Li Li Ji
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Muscle Atrophy ◽  
Mitochondrial Biogenesis ◽  
Skeletal Muscle Atrophy ◽  
Control Group ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Protein Loss ◽  
Peroxisome Proliferator Activated Receptor

Prolonged immobilization (IM) results in skeletal muscle atrophy accompanied by increased reactive oxygen species (ROS) generation, inflammation, and protein degradation. However, the biological consequence of remobilizing such muscle has been studied only sparsely. In this study, we examined the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-controlled mitochondrial biogenesis pathway and inflammatory response in mice subjected to 2 wk of hindlimb IM followed by 5 days of remobilization (RM). We hypothesized that ROS generation and activation of redox-sensitive signaling pathways play important roles in the etiology of muscle injury. FVB/N mice (age 2 mo) were randomly assigned to either 14 days of IM by casting one of the hindlimbs ( n = 7), IM followed by 5 days of RM with casting removed ( n = 7), or to a control group (Con; n = 7). Muscle to body weight ratios of three major leg muscles were significantly decreased as a result of IM. Two ubiquitin-proteasome pathway enzymes, muscle atrophy F-box (MAFb or atrogin-1) and muscle ring finger-1 (MuRF-1), were upregulated with IM and maintained at high levels during RM. Protein contents of PGC-1α and nuclear respiratory factors 1 and 2 in tibialis anterior (TA) muscle were reduced by 50% ( P < 0.01) in IM vs. Con, with no recovery observed during RM. IM suppressed mitochondrial transcription factor A and cytochrome- c content by 57% and 63% ( P < 0.01), respectively, and cytochrome- c oxidase activity by 58% ( P < 0.05). Furthermore, mitochondrial DNA content was reduced by 71% ( P < 0.01) with IM. None of these changes were reversed after RM. With RM, TA muscle showed a 2.3-fold ( P < 0.05) higher H2O2 content and a 4-fold ( P < 0.01) higher 8-isoprostane content compared with Con, indicating oxidative stress. Tumor necrosis factor-α and interleukin-6 levels in TA muscle were 4- and 3-fold higher ( P < 0.05), respectively, in IM and RM vs. CON. The nuclear factor-κB (NF-κB) pathway activation was observed only after RM, but not after IM alone. These data indicate an increase in ROS generation during the initial phase of muscle RM that could activate the NF-κB pathway, and elicit inflammation and oxidative stress. These events may hinder muscle recovery from IM-induced mitochondrial deterioration and protein loss.

scholarly journals Dietary Supplementation With Montmorency Tart Cherries and Exercise Improves Lean Mass in Older C57BL/6 Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 45-45
Author(s):  
Kara Robinson ◽  
Bethany Hatter ◽  
Karley Washburn ◽  
James Bothwell ◽  
Kendall Anderson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Muscle Mass ◽  
Mitochondrial Biogenesis ◽  
Lean Mass ◽  
Treadmill Running ◽  
Peroxisome Proliferator ◽  
Research Committee ◽  
Peroxisome Proliferator Activated Receptor ◽  
Young Mice

Abstract Objectives Sarcopenia, the progressive loss of muscle mass and strength, accelerates with age. Current recommendations to prevent sarcopenia focus on exercise and protein intake. Tart cherry (TC) has shown beneficial effects on muscle recovery following exercise. In this study, we investigated the effects of TC alone and in combination with exercise on lean mass, mitochondrial biogenesis, and oxidative stress in young compared to older mice. Methods In two cohorts (6 & 52 wk-old), female C57BL/6 mice were randomly assigned to 4 groups in a 2 × 2 factorial design with diet (AIN-93 control or TC supplemented at 10% w/w) and exercise as factors. Exercise consisted of treadmill running for 30 min, 5 d/wk, at 12 m/min and a 5° incline. Food intake was recorded daily and body weights weekly. After 8 wks, body composition was assessed using dual-energy x-ray absorptiometry. The gastrocnemius muscle was collected for protein analysis. Western blotting techniques were used to probe for superoxide dismutase 2 (SOD2) and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1a), indicators of oxidative stress and mitochondrial biogenesis. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as loading control. Data were analyzed using 2-way ANOVA with α = 0.05. Results In young mice, TC had no effect on body weight and % lean mass, but led to decreased (P &lt; 0.05) % fat mass compared to controls. Exercise decreased (P &lt; 0.05) body weight and % fat, and tended to increase (P = 0.069) % lean mass. In contrast, TC and exercise independently decreased body weight and % fat, and increased % lean mass in older mice compared to controls. The combination of TC and exercise tended to have a synergistic effect on % lean mass (P = 0.056). Preliminary results show that TC significantly up-regulated SOD2 protein expression in young mice, but no effect was observed with exercise or combined treatments. PGC1α expression tended to be suppressed (P = 0.064) in young animals fed TC. To date, we have been unable to detect changes in SOD2 and PGC1α in older mice. Conclusions TC had a protective effect on lean tissue in older mice, preliminary analyses revealed no alterations in oxidative stress or mitochondrial biogenesis. Further investigation is warranted to understand the benefits of TC on lean muscle mass in older mice. Funding Sources Cherry Research Committee of the Cherry Marketing Institute

Abstract 292: Brain Derived Neurotrophic Factor Induced Upregulation Of Peroxisome Proliferator-activated Receptor Gamma Coactivator 1-alpha Signaling Prevents Hearts From Heart Failure Progression Against Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ning Feng ◽  
Guangshuo Zhu ◽  
vidhya Sivakumaran ◽  
Manling Zhang ◽  
Djahida Bedja ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Function ◽  
Mitochondrial Biogenesis ◽  
Neurotrophic Factor ◽  
Pressure Overload ◽  
Brain Derived Neurotrophic Factor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bdnf Signaling

Background: The heart is under the influence of neurotrophins (NTs) secreted from peripheral sympathetic nerves, including brain derived neurotrophic factor (BDNF). BDNF is indispensible for cardiac development and vascular wall integrity. Yet, whether BDNF signaling plays a role in governing cardiac function in response to stress is unclear. Hypothesis: BDNF signaling contributes to maintain proper cardiac structure/function in pressure overloaded mice. Results: BDNF expression is markedly down-regulated in hearts subjected to transverse aortic constriction (TAC). Cardiac specific over-expression of BDNF (BDNF-TG) or administration of a BDNF-mimetic agonist (LM22A-4) preserved cardiac function against pressure overload. In contrast, cardiac-selective deletion of the BDNF receptor, Tropomyosin related kinase receptor B (TrkB), further exacerbated heart failure. In neurons, BDNF up-regulates Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that regulates energy metabolism and mitochondrial function/biogenesis. Oxidative stress is a major negative modulator of PGC-1a expression/activity. Exposing neonatal rat ventricular myocytes (NRVMs) to hydrogen peroxide downregulated PGC-1α, and BDNF restored it to normal levels, with a concomitant up-regulation of downstream genes involved in both mitochondrial biogenesis and oxidative stress, resulting in attenuated ROS production and increased mitochondrial biogenesis. Consistent with the cultured myocyte findings, PGC-1α and downstream genes were up-regulated in BDNF-TG mice subjected to TAC, associated with attenuated oxidative stress and improved mitochondrial biogenesis; whereas TrkB-/- mice subjected to TAC displayed further decreased PGC-1α expression with worsened oxidative stress and impaired mitochondrial biogenesis. Conclusion: Our data show that BDNF confers protection against pressure overload via enhanced PGC-1α signaling that in turn prevents oxidative stress and improves mitochondrial biogenesis. Our data suggest BDNF/trkB is a promising new therapeutic avenue to prevent or retard heart failure.

Sign in / Sign up

Export Citation Format

Share Document