Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson's disease model

Carta, Annarosa; Frau, Lucia; Pisanu, Augusta; Wardas, Jadwiga; Spiga, Saturnino; Carboni, Ezio

doi:10.1016/j.neuroscience.2011.07.046

Cited by 128 publications

(95 citation statements)

References 73 publications

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“…Our results with PPAR-γ-ir and TH-ir nigral cell counts with and without MPTP, as well as a lack of colabeling of PPAR-γ and HLA-DR are in contrast with a study by Carta and colleagues 31 , where MPTP-treated mice displayed an increase in PPAR-γ-ir, as well as an increase in the ratio of PPAR-γ/TH-ir and PPAR-γ/cd11b-ir in the SN compared to vehicle-treated animals. Differences in species and experimental design may account for the disparate results.…”

Section: Discussioncontrasting

confidence: 99%

Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Swanson

Emborg

2013

Neurological Research

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OBJECTIVE To characterize the distribution of Peroxisome proliferator-activated receptor-gamma (PPAR-γ) in the substantia nigra of normal and MPTP-treated hemiparkinsonian monkeys, in order to validate PPAR-γ as a target for neuroprotection. METHODS Immunohistochemical analysis of PPAR-γ expression was performed in the substantia nigra and other select brain regions of fifteen rhesus monkeys including controls (n = 3), hemiparkinsonian necropsied after 3 (n = 5) or 12 months (n = 3) after MPTP, and animals who received MPTP + 5 mg/kg of the PPAR-γ agonist pioglitazone (n = 4). RESULTS PPAR-γ expression was prominent in the subthalamic nucleus, oculomotor nucleus, ventral tegmental nucleus and to a lesser extent in the putamen; three or twelve months after MPTP, only the lesioned putamen had increased PPAR-γ. Stereological cell quantification in normal subjects showed that approximately 50% of neurons in the substantia nigra pars compacta (SNpc) expressed PPAR-γ. After MPTP there was a significant loss of dopaminergic (DA) neurons in the ipsilateral SNpc and the actual number of TH and PPAR-γ cells were not significantly different at either time point. Pioglitazone dosing protected TH positive neurons, closely matching the number of PPAR-γ expressing cells in the ipsilateral SNpc. Nigral immunofluorescence verified colocalization of PPAR-γ in neurons. DISCUSSION These results demonstrate that PPAR-γ is expressed in the SNpc and putamen of nonhuman primates and, that the DA nigral neurons expressing PPAR-γ are more likely to survive neurotoxin challenge after ligand activation by pioglitazone, therefore providing neuroanatomical validation for the use of PPAR-γ agonists in PD.

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Section: Discussioncontrasting

confidence: 99%

Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Swanson

Emborg

2013

Neurological Research

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“…Mice terminated at day 14 were gavaged once daily with either corn oil (vehicle control) or 50 mg/kg of each respective C-DIM compound dissolved in corn oil (MPTPp14d 1 C-DIM5, MPTPp14d 1 C-DIM8, MPTPp14d 1 C-DIM12). Treatment with MPTPp in this model causes initial loss of dopamine neurons and a sustained neuroinflammatory response that causes further loss of dopamine neurons even after treatment with MPTPp has ceased (Schintu et al, 2009;Carta et al, 2011). All animal procedures were performed in accordance with National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the Colorado State University Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

“…To determine the neuroprotective efficacy of C-DIM compounds in a relevant animal model of PD, we used a subacute administration strategy with MPTP and probenecid in mice to induce modest loss of dopamine neurons over a 7-day period, after which neuronal loss continued for an additional 7 days in the absence of MPTPp exposure, indicating a progressive neuroinflammatory lesion (Hirsch and Hunot, 2009;Schintu et al, 2009;Carta et al, 2011). Administration of C-DIM5 or C-DIM12 attenuated this progressive loss of neurons in the SN after the initial neurotoxin-induced lesion ( Fig.…”

Section: Tablementioning

confidence: 99%

“…Small molecule therapeutics with a central nervous system (CNS) indication have lower approval rates and longer development periods, compared with compounds targeted to peripheral tissues (Glass et al, 2010), contributing to the current lack of neuroprotective modalities for treating neurodegenerative disorders. Furthermore, poor performance of translational animal models of neurodegeneration in predicting clinical outcomes has limited the progress of therapeutic development for CNS disorders (Schintu et al, 2009;Carta et al, 2011). Thus, a great need exists for orally bioavailable drugs for treatment of diseases, such as Alzheimer's, Parkinson's disease (PD), amyotrophic lateral sclerosis, and multiple sclerosis (Polazzi and Monti, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-InflammatoryPara-Phenyl Substituted Diindolylmethanes in a Mouse Model of Parkinson’s Disease

Miranda

Miller

Hansen

et al. 2013

J Pharmacol Exp Ther

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There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(39-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(39-indolyl)-1-(phenyl)methane, 1,1-bis(39-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(39-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, C max , and T max levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration.

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“…sc-7196, USA) and proper secondary antibody. To enhance PPARγ signal, a three-step indirect labeling was performed combining biotinylated donkey IgG (1:500, Jackson Immuno-Research, Europe, UK) and streptavidin fluorescein conjugate [52](1:400, Vector, USA). 5µM Hoechst 33258 solution (Sigma, Italy) was used as nuclear counterstaining.…”

Section: Methodsmentioning

confidence: 99%

Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats

Bahillo

Morgese

Pisanu

et al. 2015

Neurobiology of Disease

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Long-term administration of L-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson’s disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb and oro-facial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) [1]. In this study, we showed that stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268 and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa antiparkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID.

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Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson's disease model

Cited by 128 publications

References 73 publications

Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-InflammatoryPara-Phenyl Substituted Diindolylmethanes in a Mouse Model of Parkinson’s Disease

Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats

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