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1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
2.
Elife ; 92020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32589144

RESUMO

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Encefalite/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
3.
CNS Neurosci Ther ; 26(6): 636-649, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31828969

RESUMO

AIM: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. DISCUSSION: We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. CONCLUSION: In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

4.
Neurobiol Dis ; 130: 104528, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295555

RESUMO

Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Concussão Encefálica/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Fisostigmina/análogos & derivados , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Concussão Encefálica/metabolismo , Concussão Encefálica/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fisostigmina/farmacologia , Fisostigmina/uso terapêutico
5.
Cell Transplant ; 28(9-10): 1183-1196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31177840

RESUMO

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer's disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.


Assuntos
Comportamento Animal/efeitos dos fármacos , Contusão Encefálica , Fármacos Neuroprotetores/farmacologia , Fisostigmina/análogos & derivados , Animais , Contusão Encefálica/tratamento farmacológico , Contusão Encefálica/metabolismo , Contusão Encefálica/patologia , Contusão Encefálica/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Camundongos , Microglia/metabolismo , Microglia/patologia , Fisostigmina/farmacologia , Fatores de Tempo
6.
Neurobiol Dis ; 124: 439-453, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30471415

RESUMO

Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time-dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross-validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions.


Assuntos
Concussão Encefálica/patologia , Exenatida/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Preparações de Ação Retardada , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-Dawley
7.
Sci Rep ; 8(1): 13953, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209317

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

8.
Sci Rep ; 8(1): 10722, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013201

RESUMO

We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -mediated dopaminergic neurodegeneration. The use of GLP-1 or Exendin-4 for Parkinson's disease (PD) patients is limited by their short half-lives. The purpose of this study was to evaluate a new extended release Exendin-4 formulation, PT302, in a rat model of PD. Subcutaneous administration of PT302 resulted in sustained elevations of Exendin-4 in plasma for >20 days in adult rats. To define an efficacious dose within this range, rats were administered PT302 once every 2 weeks either before or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamine-induced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Exendin-4 levels and brain tyrosine hydroxylase immunoreactivity (TH-IR). PT302 significantly increased TH-IR in the lesioned substantia nigra and striatum. There was a significant correlation between plasma Exendin-4 levels and TH-IR in the substantia nigra and striatum on the lesioned side. Our data suggest that post-treatment with PT302 provides long-lasting Exendin-4 release and reduces neurodegeneration of nigrostriatal dopaminergic neurons in a 6-hydroxydopamine rat model of PD at a clinically relevant dose.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Exenatida/administração & dosagem , Incretinas/administração & dosagem , Doença de Parkinson Secundária/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Animais , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/imunologia , Corpo Estriado/patologia , Preparações de Ação Retardada/administração & dosagem , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Masculino , Oxidopamina/administração & dosagem , Oxidopamina/toxicidade , Doença de Parkinson Secundária/etiologia , Doença de Parkinson Secundária/imunologia , Doença de Parkinson Secundária/patologia , Ratos , Ratos Sprague-Dawley , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/imunologia , Substância Negra/patologia , Resultado do Tratamento , Tirosina 3-Mono-Oxigenase/imunologia
9.
Br J Pharmacol ; 175(16): 3298-3314, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29570770

RESUMO

BACKGROUND AND PURPOSE: Microglial phenotype and phagocytic activity are deregulated in Parkinson's disease (PD). PPARγ agonists are neuroprotective in experimental PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPARγ agonist MDG548. EXPERIMENTAL APPROACH: Murine microglial cell line MMGT12 was stimulated with LPS and/or MDG548, and their effect on phagocytosis of fluorescent microspheres or necrotic neurons was investigated by flow cytometry. Cytokines and markers of microglia phenotype, such as mannose receptor C type 1; MRC1), Ym1 and CD68 were measured by elisa and fluorescent immunohistochemistry. Levels of Beclin-1, which plays a role in microglial phagocytosis, were measured by Western blotting. In the in vivo MPTP-probenecid (MPTPp) model of PD in mice, MDG548 was tested on motor impairment, nigral neurodegeneration, microglial activation and phenotype. KEY RESULTS: In LPS-stimulated microglia, MDG548 increased phagocytosis of both latex beads and necrotic cells, up-regulated the expression of MRC1, CD68 and to a lesser extent IL-10, while blocking the LPS-induced increase of TNF-α and iNOS. MDG548 also induced Beclin-1. Chronic MPTPp treatment in mice down-regulated MRC1 and TGF-ß and up-regulated TNF-α and IL-1ß immunoreactivity in activated CD11b-positive microglia, causing the death of nigral dopaminergic neurons. MDG548 arrested MPTPp-induced cell death, enhanced MRC1 and restored cytokine levels. CONCLUSIONS AND IMPLICATIONS: This study adds a novel mechanism for PPARγ-mediated neuroprotection in PD and suggests that increasing phagocytic activity and anti-inflammatory markers may represent an effective disease-modifying approach.


Assuntos
Microglia/efeitos dos fármacos , Neuroproteção/fisiologia , PPAR gama/agonistas , Transtornos Parkinsonianos/metabolismo , Fagocitose/efeitos dos fármacos , Tiobarbitúricos/farmacologia , Animais , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Microesferas , PPAR gama/metabolismo , Fenótipo
10.
Exp Neurol ; 286: 83-92, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27697481

RESUMO

Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Encefalite/induzido quimicamente , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/sangue , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/efeitos adversos , Lateralidade Funcional/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Levodopa/administração & dosagem , Levodopa/sangue , Lipopolissacarídeos/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/sangue , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Simpatolíticos/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Neurobiol Dis ; 71: 280-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25134730

RESUMO

Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine production. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-ß and IL-10, within Iba-1-positive cells in the substantia nigra compacta (SNc). In addition, to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine production and phenotype in peripheral macrophages. Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was associated with a gradual increase in both TNF-α and IL-1ß colocalization with Iba-1-positive cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-ß colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1ß colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-ß and IL-10 colocalization compared with the MPTPp treatment. CD206 was gradually reduced by the chronic MPTPp treatment, while rosiglitazone restored control levels, suggesting that M2 anti-inflammatory microglia were stimulated and inflammatory microglia were inhibited by the neuroprotective treatment. The results show that the dopaminergic degeneration was associated with a gradual microglia polarization to the inflammatory over the anti-inflammatory phenotype in a chronic mouse model of PD. Neuroprotective treatment with rosiglitazone modulated microglia polarization, boosting the M2 over the pro-inflammatory phenotype. PPAR-γ agonists may offer a novel approach to neuroprotection, acting as disease-modifying drugs through an immunomodulatory action in the CNS.


Assuntos
Citocinas/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/patologia , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Tiazolidinedionas/uso terapêutico , Animais , Contagem de Células , Polaridade Celular/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Intoxicação por MPTP/metabolismo , Camundongos , Microglia/classificação , Microglia/metabolismo , Degeneração Neural/etiologia , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/farmacologia , RNA Mensageiro/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo
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