Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis

Kiaei, Mahmoud; Kipiani, Khatuna; Chen, Junyu; Calingasan, Noel Y.; Beal, M. Flint

doi:10.1016/j.expneurol.2004.10.007

Cited by 201 publications

(146 citation statements)

References 31 publications

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“…[4][5][6]27 MPO activity and levels of TNFa and IL-1b were significantly increased in the spinal cord tissue of injured rats compared with sham-operated animals 24 h after injury in the present study. In a finding similar to other studies, [17][18][19][20]24 rosiglitazone treatment significantly reduced these increased levels of MPO, TNFa and IL-1b in the present study, thus protecting the spinal cord against secondary degeneration caused by inFammation. It is thought that TZDs confer their neuroprotective effects via the prevention of both microglial activation and inFammatory cytokine/chemokine expression, 28 in concurrence with the findings of the present study.…”

Section: Discussionsupporting

confidence: 79%

“…[12][13][14] Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor-g (PPARg) that is used in the treatment of type 2 diabetes, although its use is restricted due to sideeffects including increased risk of stroke and heart failure. 15,16 The anti-inflammatory and antioxidant properties of rosiglitazone have been studied in models of central nervous system injury and disease, including amyotrophic lateral sclerosis, 17 Parkinson's disease 18 and cerebral ischaemia or haemorrhage. 19 Rosiglitazone has also been shown to prevent apoptosis in experimental traumatic brain injury.…”

Section: Introductionmentioning

confidence: 99%

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Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury

et al. 2013

J Int Med Res

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Objective: To investigate the neuroprotective effects of rosiglitazone in a rat traumatic spinal cord injury (SCI) model. Methods: Adult Sprague-Dawley rats (n ¼ 12/group) underwent laminectomy (sham), SCI, SCI and rosiglitazone treatment (2 mg/kg twice daily for 7 days), or SCI and saline injection (vehicle). SCI was induced via dural application of an aneurysm clip. Spinal cord apoptosis and levels of tumour necrosis factor-a (TNFa), interleukin (IL)-1b, myeloperoxidase (MPO) and the apoptosisassociated proteins B-cell leukaemia/lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) were examined 24 h after SCI. Locomotor function was evaluated 3, 7, 10, 14 and 21 days after SCI. Results: At 24 h after SCI, apoptosis and TNFa, IL-1b and MPO concentrations were significantly lower in the rosiglitazone group than in the vehicle and SCI groups. SCI resulted in an increase in Bax and a decrease in Bcl-2, which was reversed by rosiglitazone treatment. Rats in the rosiglitazone group had significantly better functional recovery than those in the vehicle and SCI groups. Conclusion: Rosiglitazone signiEcantly improved functional recovery, probably via attenuation of the local inflammatory reaction and reduced apoptosis.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury

et al. 2013

J Int Med Res

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“…Additionally, one of the most interesting things that we observed was that the PPAR␥-induced protection correlated with improved mitochondrial function (22). PPAR␥ activation has been proposed to increase mitochondrial biogenesis in vivo (25), and treatment with PPAR␥ agonists has been proven successful in ameliorating neurodegenerative damage in ischemia and ALS (16,37). Therefore, our aim was to determine if PPAR␥ activation could ameliorate the mutant huntingtin-induced mitochondrial dysfunction observed by our group (6,28) and others (5,26,38).…”

Section: Mutant Huntingtin Expression Significantly Affects the Ppar␥mentioning

confidence: 98%

“…amyotrophic lateral sclerosis (16). TZDs have been proposed as potential therapeutic agents for both AD and multiple sclerosis (17), and most of their neuroprotective effects are ascribed to either improved insulin sensitivity, or to their anti-inflammatory action through PPAR␥ activation in glial cells (18,19).…”

mentioning

confidence: 99%

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Quintanilla

Jin

Fuenzalida

et al. 2008

Journal of Biological Chemistry

116

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Peroxisome proliferator-activated receptor-␥ (PPAR␥) is a member of the PPAR family of transcription factors. Synthetic PPAR␥ agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR␥ activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR␥ activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh Q7/Q7 ) or mutant (STHdh Q111/Q111 ) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR␥ activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR␥, as all protective effects were prevented by the PPAR␥ antagonist GW9662. Additionally, the PPAR␥ signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR␥ expression and reduced PPAR␥ transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR␥ pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR␥ activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.

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“…PPAR-gamma activation in macrophages was shown to reduce the expression of TNF-alpha and iNOS, thus limiting the inflammatory damage and improving cognition AD patients (42,56). TZDs have been shown to be beneficial in several cellular and animal models of CNS diseases where inflammation is a major component of the progressive neurological deficit (54,55,56,65,119). Their efficacy in improving insulin sensitivity correlates with the reduction of diabetes-induced acute brain damage, since chronic hyperglycemia is a major risk factor for neuropathy and vasculopathy (81).…”

mentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

373

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis

Cited by 201 publications

References 31 publications

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

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