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1.
Anesth Analg ; 133(5): 1140-1151, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34673725

RESUMO

BACKGROUND: Parkinson disease is a chronic and progressive movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The causes of Parkinson disease are not clear but may involve genetic susceptibilities and environmental factors. As in other neurodegenerative disorders, individuals predisposed to Parkinson disease may have an accelerated onset of symptoms following perioperative stress such as anesthesia, surgery, pain, and inflammation. We hypothesized that anesthesia alone accelerates the onset of Parkinson disease-like pathology and symptoms. METHODS: A presymptomatic Parkinson rat model (the protein, DJ-1, encoded by the Park7 gene [DJ-1], PARK7 knockout) was exposed to a surgical plane of isoflurane or 20% oxygen balanced with nitrogen for 2 hours on 3 occasions between 6 and 7 months of age. Acute and long-term motor and neuropathological effects were examined from 7 to 12 months of age in male DJ-1 rats, using the ladder rung, rotarod, and novel object recognition assays, as well as the immunohistochemical localization of tyrosine hydroxylase in dopaminergic neurons in the substantia nigra and ionized calcium-binding adaptor protein-1 (Iba-1) microglial activation in the substantia nigra and hippocampus. RESULTS: In the acute group, after the third anesthetic exposure at 7 months of age, the isoflurane group had a significant reduction in the density of dopaminergic neurons in the SNpc compared to controls. However, this reduction was not associated with increased microglial activation in the hippocampus or substantia nigra. With the ladder rung motor skills test, there was no effect of anesthetic exposure on the total number of foot faults or the ladder rung pattern in the acute group. The rotarod test also detected no differences before and after the third exposure in controls. For the long-term group, immunohistochemical analyses detected no differences in the density of dopaminergic neurons or microglial cells compared to unexposed DJ-1 rats from 8 to 12 months of age. The ladder rung test in the long-term group showed no differences in the total number of foot faults with time and exposure or between ladder rung patterns. The rotarod test detected no significant effect of exposure with time or between groups at any time point. The novel object recognition task in the long-term group revealed no differences in short- or long-term memory or in the number of rearings as a function of exposure. CONCLUSIONS: Multiple isoflurane exposures in this rat model of Parkinson disease transiently enhanced dopaminergic neurodegeneration in the SNpc that resolved over time and had no effects on progression in this Parkinson disease-like phenotype.


Assuntos
Anestésicos Inalatórios/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Isoflurano/toxicidade , Degeneração Neural , Transtornos Parkinsonianos/induzido quimicamente , Parte Compacta da Substância Negra/efeitos dos fármacos , Proteína Desglicase DJ-1/genética , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Técnicas de Inativação de Genes , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Teste de Campo Aberto/efeitos dos fármacos , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Proteína Desglicase DJ-1/deficiência , Ratos Long-Evans , Ratos Transgênicos , Teste de Desempenho do Rota-Rod , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismo
2.
Nat Commun ; 12(1): 5569, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552093

RESUMO

Deep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson's disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors.


Assuntos
Estimulação Encefálica Profunda/métodos , Nanopartículas de Magnetita/uso terapêutico , Transtornos Parkinsonianos/terapia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Oxidopamina/efeitos adversos , Transtornos Parkinsonianos/induzido quimicamente , Núcleo Subtalâmico/fisiologia , Canais de Cátion TRPV/metabolismo
3.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502404

RESUMO

Rodent models of Parkinson's disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1-/-SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.


Assuntos
Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Doença de Parkinson/fisiopatologia , Animais , Encéfalo/patologia , Corpo Estriado/metabolismo , Toxina Diftérica/metabolismo , Toxina Diftérica/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
4.
Cells ; 10(8)2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34440619

RESUMO

The oxidative-stress-induced impairment of autophagy plays a critical role in the pathogenesis of Parkinson's disease (PD). In this study, we investigated whether the alteration of Nrf2 in astrocytes protected against 6-OHDA (6-hydroxydopamine)- and rotenone-induced PD-like phenotypes, using 6-OHDA-induced rat PD and rotenone-induced Drosophila PD models. In the PD rat model, we found that Nrf2 expression was significantly higher in astrocytes than in neurons. CDDO-Me (CDDO methyl ester, an Nrf2 inducer) administration attenuated PD-like neurodegeneration mainly through Nrf2 activation in astrocytes by activating the antioxidant signaling pathway and enhancing autophagy in the substantia nigra and striatum. In the PD Drosophila model, the overexpression of Nrf2 in glial cells displayed more protective effects than such overexpression in neurons. Increased Nrf2 expression in glial cells significantly reduced oxidative stress and enhanced autophagy in the brain tissue. The administration of the Nrf2 inhibitor ML385 reduced the neuroprotective effect of Nrf2 through the inhibition of the antioxidant signaling pathway and autophagy pathway. The autophagy inhibitor 3-MA partially reduced the neuroprotective effect of Nrf2 through the inhibition of the autophagy pathway, but not the antioxidant signaling pathway. Moreover, Nrf2 knockdown caused neurodegeneration in flies. Treatment with CDDO-Me attenuated the Nrf2-knockdown-induced degeneration in the flies through the activation of the antioxidant signaling pathway and increased autophagy. An autophagy inducer, rapamycin, partially rescued the neurodegeneration in Nrf2-knockdown Drosophila by enhancing autophagy. Our results indicate that the activation of the Nrf2-linked signaling pathways in glial cells plays an important neuroprotective role in PD models. Our findings not only provide a novel insight into the mechanisms of Nrf2-antioxidant-autophagy signaling, but also provide potential targets for PD interventions.


Assuntos
Antioxidantes/metabolismo , Astrócitos/metabolismo , Autofagia , Proteínas de Drosophila/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Degeneração Neural , Transtornos Parkinsonianos/metabolismo , Proteínas Repressoras/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Animais Geneticamente Modificados , Antiparkinsonianos/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Autofagia/efeitos dos fármacos , Comportamento Animal , Di-Hidroxifenilalanina/análogos & derivados , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Masculino , Atividade Motora , Fator 2 Relacionado a NF-E2/genética , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Fenótipo , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Rotenona , Transdução de Sinais , Sirolimo/farmacologia
6.
Cell Death Dis ; 12(7): 674, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226513

RESUMO

Parkinson's disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.


Assuntos
Autofagia , Encéfalo/patologia , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/prevenção & controle , Células de Schwann/transplante , Transplante de Células-Tronco , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Fenótipo , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Pele/citologia , Serina-Treonina Quinases TOR/metabolismo
7.
Sci Rep ; 11(1): 15185, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312413

RESUMO

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disease of the central nervous system. Early treatment for PD is efficient; however, long-term systemic medication commonly leads to deleterious side-effects. Strategies that enable more selective drug delivery to the brain using smaller dosages, while crossing the complex brain-blood barrier (BBB), are highly desirable to ensure treatment efficacy and decrease/avoid unwanted outcomes. Our goal was to design and test the neurotherapeutic potential of a forefront nanoparticle-based technology composed of albumin/PLGA nanosystems loaded with dopamine (ALNP-DA) in 6-OHDA PD mice model. ALNP-DA effectively crossed the BBB, replenishing dopamine at the nigrostriatal pathway, resulting in significant motor symptom improvement when compared to Lesioned and L-DOPA groups. Notably, ALNP-DA (20 mg/animal dose) additionally up-regulated and restored motor coordination, balance, and sensorimotor performance to non-lesioned (Sham) animal level. Overall, ALNPs represent an innovative, non-invasive nano-therapeutical strategy for PD, considering its efficacy to circumvent the BBB and ultimately deliver the drug of interest to the brain.


Assuntos
Barreira Hematoencefálica/metabolismo , Dopamina/administração & dosagem , Dopamina/farmacocinética , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanotecnologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
8.
J Neurochem ; 158(3): 779-797, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107061

RESUMO

Clinical diagnosis of Parkinson's disease (PD) occurs typically when a substantial proportion of dopaminergic neurons in the substantia nigra (SN) already died, and the first motor symptoms appear. Therefore, tools enabling the early diagnosis of PD are essential to identify early-stage PD patients in which neuroprotective treatments could have a significant impact. Here, we test the utility and sensitivity of the diffusion kurtosis imaging (DKI) in detecting progressive microstructural changes in several brain regions of mice exposed to chronic intragastric administration of rotenone, a mouse model that mimics the spatiotemporal progression of PD-like pathology from the ENS to the SN as described by Braak's staging. Our results show that DKI, especially kurtosis, can detect the progression of pathology-associated changes throughout the CNS. Increases in mean kurtosis were first observed in the dorsal motor nucleus of the vagus (DMV) after 2 months of exposure to rotenone and before the loss of dopaminergic neurons in the SN occurred. Remarkably, we also show that limited exposure to rotenone for 2 months is enough to trigger the progression of the disease in the absence of the environmental toxin, thus suggesting that once the first pathological changes in one region appear, they can self-perpetuate and progress within the CNS. Overall, our results show that DKI can be a useful radiological marker for the early detection and monitoring of PD pathology progression in patients with the potential to improve the clinical diagnosis and the development of neuroprotective treatments.


Assuntos
Imagem de Tensor de Difusão/métodos , Progressão da Doença , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Rotenona/toxicidade , Administração Oral , Animais , Inseticidas/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Rotenona/administração & dosagem , Fatores de Tempo
9.
BMC Psychiatry ; 21(1): 289, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082747

RESUMO

BACKGROUND: Parkinsonian symptoms are common adverse effects of antipsychotics. Older adults are particularly vulnerable to drug-induced parkinsonism. Nonetheless, parkinsonian symptoms in seniors treated with antipsychotics cannot be straightforwardly attributed to antipsychotic medication. A comprehensive diagnostic workup is necessary in many cases in order to shed light on the cause of such symptoms in this patient population. CASE SERIES: Eight cases of hospitalized depressed older adults with parkinsonian symptoms, who were treated for at least one year with antipsychotics, are reported. Based on neurological consultation, structural brain imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (SPECT), Parkinson's disease was diagnosed in one case, idiopathic tremor in another, vascular parkinsonism in another one, while in another individual parkinsonian symptoms persisted at 12-month post-discharge follow-up even though his/her symptoms were classified as drug-induced on discharge. In four patients, parkinsonian symptoms were definitely drug-induced and no movement disturbances were reported at follow-up. CONCLUSIONS: Differences in the cause and outcome of parkinsonian symptoms in seniors treated with antipsychotics merit systematic and in-depth study considering the therapeutic and prognostic implications of an accurate detection of the cause of such symptoms. Familiarizing clinical psychiatrists with these differences could pave the way towards approaching seniors with severe, atypical and/or persistent parkinsonian symptoms in a more individualized diagnostic and therapeutic manner, and towards more cautious prescribing of antipsychotics in this age group.


Assuntos
Antipsicóticos , Transtornos Parkinsonianos , Assistência ao Convalescente , Idoso , Antipsicóticos/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Alta do Paciente , Tomografia Computadorizada de Emissão de Fóton Único
10.
Arch Ital Biol ; 159(2): 64-81, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34184239

RESUMO

During late stages, retinal degenerative disorders affecting photoreceptors progress independently from the specific disease trigger. In fact, a number of detrimental consequences occur downstream of photoreceptors, which are triggered by the loss of photoreceptors themselves. Such downstream anatomical alterations were originally thought to be compensatory events aimed to restore retinal function. At present, these phenomena are deciphered as detrimental effects and the term retinal degeneration is used to indicate the loss of cells and architecture within the inner retina as a consequence of damage to photoreceptors. In the process of testing a photoreceptor-dependent downstream spreading of neurodegeneration we applied a neurotoxin mimicking Parkinson's disease (PD), 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP). Chronic MPTP administration produces degeneration within the mouse retina. This is evident by apoptosis quite circumscribed to photoreceptors, which is reminiscent of most phenotypes of retinal degeneration. Retinal pathology following plain HE histochemistry is more widespread with delamination and loss of neuronal packaging in the inner retina. The retinal damage is characterized by a marked synucleinopathy mostly within retinal ganglion cells. In contrast, dopamine-containing structures are intact while norepinephrine is significantly reduced. Despite the involvement of the retina in PD is documented, no study so far analyzed the onset of a synucleinopathy and a degenerative process mimicking what is now recognized in typical retinal degeneration. The present data provide a novel vista on the reciprocal role of the retina in neurodegenerative disorders.


Assuntos
Transtornos Parkinsonianos , Degeneração Retiniana , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Dopamina , Camundongos , Neurotoxinas/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Degeneração Retiniana/induzido quimicamente
11.
Neurologist ; 26(4): 149-152, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34190209

RESUMO

INTRODUCTION: Parkinsonism-hyperpyrexia syndrome (PHS) is a rare and potentially fatal complication of Parkinson disease (PD) characterized by a neuroleptic malignant-like syndrome due to abrupt discontinuation of antiparkinsonian medications. CASE REPORT: A 79-year-old woman with late-stage PD presented at the hospital with neuropsychiatric and uncontrolled parkinsonian motor symptoms. Soon after the abrupt discontinuation of amantadine, the patient suddenly presented with global rigidity, global unresponsiveness, diaphoresis, tachycardia, recurrent hyperpyrexia, and a mildly elevated creatine kinase, which lead to the diagnosis of PHS. Amantadine was then reinitiated and her symptoms resolved within 10 days. CONCLUSIONS: Amantadine is an antiparkinsonian medication scarcely associated with PHS. The few reported cases are further summarized and discussed in this article. This case highlights the importance of early recognition of PHS, which may be caused by changes in other antiparkinson agents such as amantadine, and the need to slowly titrate such agents.


Assuntos
Síndrome Maligna Neuroléptica , Doença de Parkinson , Transtornos Parkinsonianos , Idoso , Amantadina/efeitos adversos , Antiparkinsonianos/efeitos adversos , Feminino , Humanos , Síndrome Maligna Neuroléptica/etiologia , Doença de Parkinson/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente
12.
Neurochem Res ; 46(9): 2317-2332, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34097239

RESUMO

Besides motor disorder, cognitive dysfunction is also common in Parkinson's disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD.


Assuntos
Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Silibina/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Memantina/uso terapêutico , Camundongos Endogâmicos C57BL , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/patologia , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Silibina/administração & dosagem , alfa-Sinucleína/metabolismo
13.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946908

RESUMO

Alterations of zinc homeostasis have long been implicated in Parkinson's disease (PD). Zinc plays a complex role as both deficiency and excess of intracellular zinc levels have been incriminated in the pathophysiology of the disease. Besides its role in multiple cellular functions, Zn2+ also acts as a synaptic transmitter in the brain. In the forebrain, subset of glutamatergic neurons, namely cortical neurons projecting to the striatum, use Zn2+ as a messenger alongside glutamate. Overactivation of the cortico-striatal glutamatergic system is a key feature contributing to the development of PD symptoms and dopaminergic neurotoxicity. Here, we will cover recent evidence implicating synaptic Zn2+ in the pathophysiology of PD and discuss its potential mechanisms of actions. Emphasis will be placed on the functional interaction between Zn2+ and glutamatergic NMDA receptors, the most extensively studied synaptic target of Zn2+.


Assuntos
Doença de Parkinson/fisiopatologia , Sinapses/fisiologia , Zinco/fisiologia , Animais , Gânglios da Base/fisiopatologia , Proteínas de Transporte de Cátions/deficiência , Córtex Cerebral/fisiopatologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Corpo Estriado/fisiopatologia , Feminino , Homeostase , Humanos , Líquido Intracelular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/fisiopatologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/fisiologia
14.
Toxicol Appl Pharmacol ; 423: 115558, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33961902

RESUMO

PURPOSE: Studies argue in favor of hydrogen sulfide (H2S) as the next potent therapeutic agent for neurodegenerative diseases. In present study, we investigated the effect of long term treatment with NaHS (as donor of H2S) on induction and progress of the 6-hydroxydopamine (6-OHDA) -induced Parkinsonism in rat. METHODS: The 6-OHDA was injected into medial forebrain bundle of right hemisphere by stereotaxic surgery. Behavioral tests and treatments were carried out to eight weeks after the toxin. Immunohistochemistry and western blotting were carried out to evaluate the survival of tyrosine hydroxylase (TH) -positive neurons in substantia nigra (SN) and also expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), the markers of endoplasmic reticulum (ER) stress, in striatum and SN. RESULTS: Eight weeks assessment of the behavioral symptoms showed that NaHS especially at dose of 100 µmol/kg attenuates remarkably induction of the Parkinsonism and prevents its progress. NaHS also increased the survival of TH- positive neurons and suppressed 6-OHDA- induced overexpression of GRP78 and CHOP. Blockade of ATP-sensitive potassium (K-ATP) channels with glibenclamide (Glib) prevented markedly the effect of NaHS on both the induction phase and survival of TH- positive neurons. But Glib did not affect the preventing effect of NaHS on the progress phase and its suppressing effect on the overexpression of ER stress markers. CONCLUSION: H2S attenuates induction of the 6-OHDA- induced Parkinsonism and also increases the survival of dopaminergic neurons through activation of K-ATP channels. H2S also prevents progress of the Parkinsonism probably through suppression of ER stress.


Assuntos
Progressão da Doença , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sulfeto de Hidrogênio/uso terapêutico , Canais KATP/metabolismo , Oxidopamina/toxicidade , Transtornos Parkinsonianos/metabolismo , Animais , Estresse do Retículo Endoplasmático/fisiologia , Gasotransmissores/farmacologia , Gasotransmissores/uso terapêutico , Sulfeto de Hidrogênio/farmacologia , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar
15.
Toxicol Lett ; 349: 1-11, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34052309

RESUMO

Pesticides exposure can lead to damage of dopaminergic neurons, which are associated with increased risk of Parkinson's disease (PD). However, the etiology of PD remains poorly understood and no therapeutic strategy is available. Previous studies suggested the involvement of NLRP3 inflammasome in the onset of PD. This study was designed to investigate whether glibenclamide, an inhibitor of NLRP3 inflammasome, could offer a reliable protective strategy for PD in a mouse PD model induced by paraquat and maneb. We found that glibenclamide exerted potent neuroprotection against paraquat and maneb-induced upregulation of α-synuclein, dopaminergic neurodegeneration and motor impairment in brain of mice. Mechanistically, glibenclamide treatment blocked NLRP3 inflammasome activation evidenced by reduced expressions of NLRP3, activated caspase-1 and mature interleukin-1ß in glibenclamide co-treated mice compared with those in paraquat and maneb group mice. Furthermore, glibenclamide treatment mitigated paraquat and maneb-induced microglial M1 proinflammatory response and nuclear factor-κB activation in mice. Finally, the increased superoxide production, lipid peroxidation, protein levels of NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) induced by paraquat and maneb were all attenuated by glibenclamide. Overall, our findings demonstrated that glibenclamide protected dopaminergic neurons in a mouse PD model induced by combined exposures of paraquat and maneb through suppression of NLRP3 inflammasome activation, microglial M1 polarization and oxidative stress.


Assuntos
Antiparkinsonianos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Glibureto/farmacologia , Inflamassomos/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Degeneração Neural , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Inflamassomos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Maneb , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia
16.
Food Funct ; 12(9): 4079-4091, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977962

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a disorder of both the motor and nonmotor systems due to a loss of dopaminergic (DA) neurons. Herein, we aimed to investigate the potential neuroprotective role of Schisandra chinensis (Sch) and to determine the mechanism by which Sch functions to ameliorate PD in a 6-hydroxydopamin (6-OHDA)-induced PD model. The open field test, sucrose preference test, and Y-maze test were utilized to evaluate the motor and nonmotor symptoms. We found that administration of Sch improved both disorders and DA neurodegeneration in 6-OHDA-induced mice. Additional data confirmed that Sch treatment significantly increased BDNF expression and decreased the activity of GSK-3ß in the striatum and hippocampus. Moreover, Sch was able to alleviate the abnormal levels of ROS and increase SOD by boosting Nrf2 expression. The nuclear translocation of NF-κB was inhibited by Sch, which subsequently led to a downregulation of proinflammatory cytokines. Sch effectively suppressed apoptosis by decreasing expressions of caspase 3, caspase 9, and p53 in the PD mouse model. Our findings demonstrate that Sch protects against DA neurodegeneration in 6-OHDA-induced PD mice by suppressing oxidative stress, neuroinflammation and apoptosis through the involvement of the BDNF/Nrf2/NF-κB signaling pathway.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Schisandra , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Fitoterapia , Transdução de Sinais
17.
Exp Neurol ; 342: 113741, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33965411

RESUMO

BACKGROUND: Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration. OBJECTIVES: In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing µ-opioid receptor expression. METHODS: Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [3H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and µ-opioid receptor availability were assessed with [3H]Raclopride and [3H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [3H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol. RESULTS: We confirmed a dopaminegic deficit with increased striatal [3H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [3H]UCB-J binding while [3H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [3H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic µ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold. CONCLUSION: These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.


Assuntos
Encéfalo/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/terapia , Condicionamento Físico Animal/fisiologia , Sinapses/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Teste de Esforço/métodos , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Condicionamento Físico Animal/métodos , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
18.
Exp Neurol ; 342: 113740, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33971218

RESUMO

In Parkinson's disease (PD), long-term administration of L-dopa often leads to L-dopa-induced dyskinesia (LID), a debilitating motor complication. The p75 neurotrophin receptor (p75NTR) is likely to play a critical role in the regulation of dendritic spine density and morphology and appears to be associated with neuroinflammation, which previously has been identified as a crucial mechanism in LID. While aberrant modifications of p75NTR in neurological diseases have been extensively documented, only a few studies report p75NTR dysfunction in PD, and no data are available in LID. Here, we explored the functional role of p75NTR in LID. In LID rats, we identified that p75NTR was significantly increased in the lesioned striatum. In 6-hydroxydopamine (6-OHDA)-hemilesioned rats, specific knockdown of striatal p75NTR levels achieved by viral vector injection into the striatum prevented the development of LID and increased striatal structural plasticity. By contrast, we found that in 6-OHDA-hemilesioned rats, striatal p75NTR overexpression exacerbated LID and facilitated striatal dendritic spine losses. Moreover, we observed that the immunomodulatory drug fingolimod attenuated LID without lessening the therapeutic efficacy of L-dopa and normalized p75NTR levels. Together, these data demonstrate for the first time that p75NTR plays a pivotal role in the development of LID and that p75NTR may act as a potential novel target for the management of LID.


Assuntos
Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Proteínas do Tecido Nervoso/biossíntese , Oxidopamina/toxicidade , Transtornos Parkinsonianos/metabolismo , Receptores de Fatores de Crescimento/biossíntese , Animais , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
19.
J Neuroinflammation ; 18(1): 88, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823877

RESUMO

BACKGROUND: It is suggested that neuroinflammation, in which activated microglial cells play a relevant role, contributes to the development of Parkinson's disease (PD). Consequently, the modulation of microglial activation is a potential therapeutic target to be taken into account to act against the dopaminergic neurodegeneration occurring in this neurological disorder. Several soluble and membrane-associated inhibitory mechanisms contribute to maintaining microglial cells in a quiescent/surveillant phenotype in physiological conditions. However, the presence of activated microglial cells in the brain in PD patients suggests that these mechanisms have been somehow overloaded. We focused our interest on one of the membrane-associated mechanisms, the CD200-CD200R1 ligand-receptor pair. METHODS: The acute MPTP experimental mouse model of PD was used to study the temporal pattern of mRNA expression of CD200 and CD200R1 in the context of MPTP-induced dopaminergic neurodegeneration and neuroinflammation. Dopaminergic damage was assessed by tyrosine hydroxylase (TH) immunoreactivity, and neuroinflammation was evaluated by the mRNA expression of inflammatory markers and IBA1 and GFAP immunohistochemistry. The effect of the modulation of the CD200-CD200R1 system on MPTP-induced damage was determined by using a CD200R1 agonist or CD200 KO mice. RESULTS: MPTP administration resulted in a progressive decrease in TH-positive fibres in the striatum and TH-positive neurons in the substantia nigra pars compacta, which were accompanied by transient astrogliosis, microgliosis and expression of pro- and anti-inflammatory markers. CD200 mRNA levels rapidly decreased in the ventral midbrain after MPTP treatment, while a transient decrease of CD200R1 mRNA expression was repeatedly observed in this brain area at earlier and later phases. By contrast, a transient increase in CD200R1 expression was observed in striatum. The administration of a CD200R1 agonist resulted in the inhibition of MPTP-induced dopaminergic neurodegeneration, while microglial cells showed signs of earlier activation in CD200-deficient mice. CONCLUSIONS: Collectively, these findings provide evidence for a correlation between CD200-CD200R1 alterations, glial activation and neuronal loss. CD200R1 stimulation reduces MPTP-induced loss of dopaminergic neurons, and CD200 deficiency results in earlier microglial activation, suggesting that the potentiation of CD200R1 signalling is a possible approach to controlling neuroinflammation and neuronal death in PD.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Microglia/metabolismo , Receptores de Orexina/deficiência , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Animais , Feminino , Imunoglobulina G/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Receptores de Orexina/agonistas , Receptores de Orexina/genética , Transtornos Parkinsonianos/induzido quimicamente
20.
J Neurosci ; 41(22): 4937-4947, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33893220

RESUMO

Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the SNc. In contrast, DA neurons in the VTA are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the NAc, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared with DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.SIGNIFICANCE STATEMENT Environmental exposures to pesticides contribute significantly to pathologic processes that culminate in Parkinson's disease (PD). The pesticide rotenone has been used to generate a PD model that replicates key features of the illness, including dopamine neurodegeneration. To date, longstanding questions remain: are there dopamine neuron subpopulations resilient to rotenone; and if so, what are the molecular determinants of this resilience? Here we show that the subpopulation of midbrain dopaminergic neurons that express the vesicular glutamate transporter 2 (VGLUT2) are more resilient to rotenone-induced neurodegeneration. Rotenone also upregulates VGLUT2 more broadly in the midbrain, suggesting that VGLUT2 expression generally confers increased resilience to rotenone. VGLUT2 may therefore be a new target for boosting neuronal resilience to prevent toxicant-induced DA neurodegeneration in PD.


Assuntos
Neurônios Dopaminérgicos/patologia , Degeneração Neural/patologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Inseticidas/toxicidade , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Endogâmicos Lew , Rotenona/toxicidade
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