RESUMO
Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.
Assuntos
Discinesias/etiologia , Discinesias/fisiopatologia , Levodopa/efeitos adversos , Resveratrol/farmacologia , Animais , Biomarcadores , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Discinesias/tratamento farmacológico , Discinesias/metabolismo , Masculino , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologiaRESUMO
OBJECTIVES: Aberrant microglial responses promote neuroinflammation in neurodegenerative diseases. However, rifampicin's effect on cognitive and motor sequelae of inflammation remains unknown. Therefore, we investigated whether rifampicin exerts neuroprotection against lipopolysaccharide (LPS)-induced cognitive and motor impairments. METHODS: A mouse model of LPS-induced cognitive and motor impairment was established. Adult C57BL/6 mice were injected intraperitoneally with 25 mg/kg rifampicin 30 min before intraperitoneal microinjection of LPS (750 µg/kg) daily until study end. Treatments and behavioral experiments were performed once daily for 7 days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced damage to the hippocampus and substantia nigra (SN). RESULTS: Rifampicin attenuated LPS-induced cognitive and motor impairments, based on performance in the behavioral tests. Rifampicin suppressed the release of pro-inflammatory mediators, including tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2 in the serum and nitric oxide (NO) in brain tissue, and cyclooxygenase-2 and inducible nitric oxide synthase levels. Immunofluorescence revealed that rifampicin inhibited LPS-induced microglial activation in the hippocampus and SN, thus protecting the neurons. Rifampicin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Rifampicin downregulated TLR4 and MyD88 protein levels and inhibited NF-κB inhibitor alpha and NF-κB inhibitor kinase beta phosphorylation, thus reducing p65 nuclear transfer by inhibiting NF-κB signaling activation in LPS-treated mice. CONCLUSION: Rifampicin protects against LPS-induced neuroinflammation and attenuates cognitive and motor impairments by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our findings might aid the development of novel therapies to treat progressive neurodegenerative diseases.
Assuntos
Disfunção Cognitiva/metabolismo , Transtornos Motores/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Rifampina/farmacologia , Rifampina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Inflamação , Mediadores da Inflamação , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Transtornos Motores/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neuroproteção/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologiaRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative condition that affects the Central Nervous System (CNS). Insect venoms show high molecular variability and selectivity in the CNS of mammals and present potential for the development of new drugs for the treatment of PD. In this study, we isolated and identified a component of the venom of the social wasp Parachartergus fraternus and evaluated its neuroprotective activity in the murine model of PD. For this purpose, the venom was filtered and separated through HPLC; fractions were analyzed through mass spectrometry and the active fraction was identified as a novel peptide, called Fraternine. We performed two behavioral tests to evaluate motor discoordination, as well as an apomorphine-induced rotation test. We also conducted an immunohistochemical assay to assess protection in TH+ neurons in the Substantia Nigra (SN) region. Group treated with 10 µg/animal of Fraternine remained longer in the rotarod compared to the lesioned group. In the apomorphine test, Fraternine decreased the number of rotations between treatments. This dose also inhibited dopaminergic neuronal loss, as indicated by immunohistochemical analysis. This study identified a novel peptide able to prevent the death of dopaminergic neurons of the SN and recover motor deficit in a 6-OHDA-induced murine model of PD.
Assuntos
Comportamento Animal/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Peptídeos/farmacologia , Substância Negra/efeitos dos fármacos , Venenos de Vespas/química , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Masculino , Camundongos , Degeneração Neural , Fármacos Neuroprotetores/isolamento & purificação , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Peptídeos/isolamento & purificação , Teste de Desempenho do Rota-Rod , Substância Negra/metabolismo , Substância Negra/fisiopatologia , VespasRESUMO
AIMS: Parkinson's disease (PD) is a neurological disorder caused by environmental and genetic factors, characterized by the death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to a decrease of dopamine in the striatum. In addition to motor symptoms, PD has several abnormalities, among which are cardiovascular changes, such as orthostatic and postprandial hypotension, and blood pressure lability. Studies demonstrate gender differences in PD pathogenesis, indicating that female hormones have a protective role against disease development. However, no studies examining cardiovascular changes in a female rat model of parkinsonism exist. MAIN METHODS: Wistar female rats were subjected to ovariectomy (OVX) or sham surgery. After seven days, these animals were subjected to bilateral infusion of 6-hydroxydopamine (6-OHDA) or vehicle solution in their SNpc. On the 14th experimental day, a femoral artery catheterization was performed to record cardiovascular parameters after 24 h in conscious state. Analyses of cardiovascular variability and spontaneous baroreflex were performed. The nitrite (NO) concentration in the heart, thoracic aorta, abdominal aorta, and plasma was measured. KEY FINDINGS: The sham-6-OHDA group had no decrease in the mean arterial pressure compared to sham-saline group, whereas the OVX-6-OHDA group presented a baseline decrease in comparison to sham-6-OHDA. The OVX-6-OHDA group showed an NO increase in the heart and abdominal aorta, whereas the sham-6-OHDA group did not. The very low frequency variability component decreased in the sham-6-OHDA but not in the OVX-6-OHDA group. SIGNIFICANCE: We suggest a cardiovascular protection by ovarian hormones in PD with a possible NO involvement.
Assuntos
Sistema Cardiovascular/fisiopatologia , Doença de Parkinson/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Animais , Pressão Sanguínea , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Frequência Cardíaca , Neostriado/fisiopatologia , Óxido Nítrico/análise , Oxidopamina/efeitos adversos , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo , Ratos , Ratos Wistar , Substância Negra/fisiopatologiaRESUMO
Parkinson's Disease (PD) is characterized by the massive loss of dopaminergic neurons, leading to the appearance of several motor impairments. Current pharmacological treatments, such as the use of levodopa, are yet unable to cure the disease. Therefore, there is a need for novel strategies, particularly those that can combine in an integrated manner neuroprotection and neuroregeneration properties. In vitro and in vivo models have recently revealed that the secretome of mesenchymal stem cells (MSCs) holds a promising potential for treating PD, given its effects on neural survival, proliferation, differentiation. In the present study, we aimed to access the impact of human bone marrow MSCs (hBM-MSCs) secretome in 6-hydroxydopamine (6-OHDA) PD model when compared to levodopa administration, by addressing animals' motor performance, and substantia nigra (SN), and striatum (STR) histological parameters by tyrosine hydroxylase (TH) expression. Results revealed that hBM-MSCs secretome per se appears to be a modulator of the dopaminergic system, enhancing TH-positive cells expression (e.g., dopaminergic neurons) and terminals both in the SN and STR when compared to the untreated group 6-OHDA. Such finding was positively correlated with a significant amelioration of the motor outcomes of 6-OHDA PD animals (assessed by the staircase test). Thus, the present findings support hBM-MSCs secretome administration as a potential therapeutic tool in treating PD, and although we suggest candidate molecules (Trx1, SEMA7A, UCHL1, PEDF, BDNF, Clusterin, SDF-1, CypA, CypB, Cys C, VEGF, DJ-1, Gal-1, GDNF, CDH2, IL-6, HSP27, PRDX1, UBE3A, MMP-2, and GDN) and possible mechanisms of hBM-MSCs secretome-mediated effects, further detailed studies are needed to carefully and clearly define which players may be responsible for its therapeutic actions. By doing so, it will be reasonable to presume that potential treatments that can, per se, or in combination modulate or slow PD may lead to a rational design of new therapeutic or adjuvant strategies for its functional modeling and repair.
Assuntos
Levodopa/uso terapêutico , Células-Tronco Mesenquimais/metabolismo , Doença de Parkinson/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Levodopa/administração & dosagem , Transplante de Células-Tronco Mesenquimais , Atividade Motora , Neostriado/patologia , Neostriado/fisiopatologia , Oxidopamina , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fenótipo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Substância Negra/patologia , Substância Negra/fisiopatologiaRESUMO
Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.
Assuntos
Disfunção Cognitiva , Putamen , Esquizofrenia , Substância Negra , Adolescente , Adulto , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Função Executiva/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória Episódica , Pessoa de Meia-Idade , Imagem Multimodal , Diester Fosfórico Hidrolases , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/enzimologia , Putamen/fisiopatologia , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/enzimologia , Esquizofrenia/fisiopatologia , Substância Negra/diagnóstico por imagem , Substância Negra/enzimologia , Substância Negra/fisiopatologia , Adulto JovemRESUMO
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been well documented in glycolytic pathway. Independent of this, it has various other functions including stimulator of programmed cell death. Reports suggest that glutamate receptor AMPA type-2 subunit (GluA2) forms protein complex with GAPDH and internalized during excitotoxicity. Further, nuclear accumulation of GluA2 and GAPDH have been studied in neurological disorders like epilepsy and multiple sclerosis, and disruption of this complex rescued neurological symptoms such as astrogliosis, AMPA mediated excitotoxicity and p53 phosphorylation. On the other hand, study on ischemic rat model showed that nucleus translocated GAPDH binds with p53 leading to apoptosis. However, the molecular events underlying these processes remained to be established in Parkinson's disease (PD). The present study focused on investigating the levels of GAPDH, GluA2 and p53 in the nuclear fraction (NF) and total homogenate (TH) of substantia nigral (SN) region obtained from post-mortem PD brains and their age-matched controls. The level of caspase 3, an apoptotic marker and mediator for p53 induced cell death was also measured. A significant increase in nuclear GAPDH, GluA2 and p53 were observed in PD SN region, compared to the controls. Similarly, increased caspase 3 level was observed in PD SN region. Data obtained from the present study suggest that nuclear accumulation of GAPDH, GluA2 and p53 plays a key role in the pathophysiology of neuronal cell death in PD. Thus decreasing nuclear translocation of these death pro-death signaling markers may attenuate neurodegeneration that aids in the development of potential therapeutic targets in the management of PD.
Assuntos
Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Doença de Parkinson/fisiopatologia , Receptores de AMPA/metabolismo , Substância Negra/fisiopatologia , Proteína Supressora de Tumor p53/metabolismo , Idoso , Autopsia , Núcleo Celular/metabolismo , Feminino , Humanos , Masculino , Doença de Parkinson/metabolismo , Substância Negra/metabolismoRESUMO
Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson's disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T α-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by α-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of α-SYN, linking neuronal activity to the pathophysiological role of α-SYN in PD.
Assuntos
Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Substância Negra/fisiopatologia , Sinapses/fisiologia , alfa-Sinucleína/metabolismo , Potenciais de Ação , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Feminino , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Ratos Wistar , Substância Negra/metabolismo , Sinapses/metabolismoRESUMO
OBJECTIVE: We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties. METHODS: Mean nigral R2* rates were measured in 40 patients with tremor-dominant Parkinson's disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls. RESULTS: Tremor-dominant PD patients had significantly higher nigral R2* values (34.1 ± 5.7) than those with tremor in dystonia (30.0 ± 3.9), essential tremor (30.6 ± 4.8), and controls (30.0 ± 2.8). An R2* threshold of 31.15 separated tremor-dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non-PD tremor patients was 67.5% and 60%. CONCLUSION: Iron content in the substantia nigra is significantly higher in tremor-dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Ferro/metabolismo , Substância Negra/metabolismo , Tremor/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Substância Negra/fisiopatologia , Tremor/fisiopatologiaRESUMO
Gintonin, a ginseng-derived glycolipoprotein isolated from ginseng, has been shown to be neuroprotective in several neurological disorders such as Alzheimer's disease models and depressive-like behaviors. In this study, we sought to investigate the potential protective mechanisms of gintonin in an in vivo MPTP and in vitro MPP+-mediated Parkinson's disease (PD) model. We hypothesized that activation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1, potential therapeutic targets for neurodegeneration) with gintonin could abrogate PD-associated neurotoxicity by modulating the accumulation of α-synuclein, neuroinflammation, and apoptotic cell death in an MPTP/MPP+ models of PD. Our in vivo and in vitro findings suggest that the neuroprotective effects of gintonin were associated with the regulation of the Nrf2/HO-1 pathway, which regulated the expression of proinflammatory cytokines and nitric oxide synthase and apoptotic markers in the substantia nigra and striatum of the mice. Moreover, the neuroprotective effects of gintonin were also associated with a reduction in α-synuclein accumulation in the mouse substantia nigra and striatum. The neuroprotective effects of gintonin were further validated by analyzing the effects of gintonin on MPP+-treated SH-SY5Y cells, which confirmed the protective effects of gintonin. It remains for future basic and clinical research to determine the potential use of gintonin in Parkinson's disease. However, to the best of our knowledge, marked alterations in biochemical and morphological setup of midbrain dopaminergic pathways by gintonin in MPTP mice model have not been previously reported. We believe that gintonin might be explored as an important therapeutic agent in the treatment of PD.
Assuntos
Corpo Estriado/patologia , Neurônios Dopaminérgicos/patologia , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais , Substância Negra/patologia , alfa-Sinucleína/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Rotenona , Transdução de Sinais/efeitos dos fármacos , Substância Negra/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Caffeic acid phenethyl ester is found in honey bee propolis. It has immunomodulatory, anti-inflammatory and anti-cancer properties. Rotenone is a pesticide commonly used for inducing experimental Parkinson's disease (PD) due to complex I inhibition and microglia activating properties. The current study examined neuroprotective effect of caffeic acid against rotenone-induced neurodegeneration in groups of seven mice. METHODS: Mice received protective doses of caffeic acid (2.5, 5 or 10 mg/kg) daily and nine injections of rotenone (1 mg kg, subcutaneously) - every 48 h. Behavioral evaluation of motor function was done by a battery of tests including open-field test, cylinder test, pole test and rotarod test; all these tests showed motor impairment. RESULTS: Assay of striatal dopamine highlighted a significant decrease and increases in inflammatory markers. In addition, histopathological assessment of substantia nigra neurons demonstrated low immunostaining for tyrosine hydroxylase (TH) in rotenone treated mice. PCR analysis highlighted upregulation for genes encoding CD11b (a microglia surface antigen), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NFκB). Treatment with caffeic acid (5 or 10 mg/kg) amended most of rotenone-induced motor deficits, lessened microglia expression and inflammatory mediators and improved the nigral TH immunostaining. CONCLUSION: These results confirmed the anti-inflammatory activity of caffeic acid and highlighted its neuroprotective activity against rotenone-induced neurodegeneration in mice.
Assuntos
Anti-Inflamatórios/farmacologia , Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Mediadores da Inflamação/metabolismo , Locomoção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Substância Negra/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Rotenona , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Reinforcement omission effects (ROEs) are characterized by higher response rates after reinforcement omission than after reinforcement delivery. This pattern of behavior is interpreted in terms of motivational and attentional processes. Recent studies from our laboratory have shown that the amygdala, nucleus accumbens, and medial prefrontal cortex are involved in ROE modulation. Also, the literature has demonstrated a role of other areas such as substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) in processes related to surprising events, such as prediction error and presentation or omission of an event (exteroceptive stimulus and reinforcement). Since these structures send projections to areas related to ROE modulation such as the amygdala, nucleus accumbens, and prefrontal cortex, the objective of the present study was to determine whether the SNc and VTA also integrate the circuit involved in ROE modulation. Rats were trained on a fixed-interval 12 s with limited-hold 6 s signaled schedule of reinforcement (Pre-lesion training). After acquisition of stable performance, the rats received bilateral neurotoxic lesions of the SNc (Experiment 1) and VTA (Experiment 2). Following postoperative recovery, the rats were submitted to two refresher sessions (Post-lesion training). Subsequently, the training was changed from a 100 to a 50% schedule of reinforcement (Post-lesion testing). In both experiments, the results showed that there was no difference in performance between sham rats and rats with bilateral lesions of the SNc or the VTA.
Assuntos
Animais , Masculino , Ratos , Reforço Psicológico , Comportamento Animal/fisiologia , Substância Negra/lesões , Área Tegmentar Ventral/lesões , Condicionamento Operante/fisiologia , Parte Compacta da Substância Negra/lesões , Substância Negra/fisiopatologia , Ratos Wistar , Área Tegmentar Ventral/fisiopatologia , Parte Compacta da Substância Negra/fisiopatologia , Aprendizagem/fisiologiaRESUMO
The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC+/- mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/- mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.
Assuntos
Receptor DCC/genética , Sistema Límbico/fisiopatologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Adulto , Envelhecimento/psicologia , Animais , Axônios , Comportamento Exploratório , Feminino , Heterozigoto , Humanos , Sistema Límbico/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Transtornos da Personalidade/genética , Transtornos da Personalidade/psicologia , Córtex Pré-Frontal/diagnóstico por imagem , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/psicologia , Substância Negra/diagnóstico por imagem , Substância Negra/fisiopatologia , Área Tegmentar Ventral/diagnóstico por imagem , Área Tegmentar Ventral/fisiopatologia , Adulto JovemRESUMO
Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease.
Assuntos
Antidepressivos/uso terapêutico , Fatores de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Regulação para Cima , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologia , Regulação para Cima/efeitos dos fármacosRESUMO
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. For decades, the unilateral 6hydroxydopamine (6OHDA) rat model has been employed to investigate the pathogenesis and therapy of PD. However, the behavior and associated pathological features of the model long term have not previously been described dynamically. In the present study, the unilateral model was established by 6OHDA injection in the striatum. The PD rat model was determined 2 weeks following surgery, according to the apomorphine (APO)induced rotations, cylinder, rotarod and open field tests. THpositive neurons and fibers in the substantia nigra pars compacta (SNpc) and striatum, respectively, and glial activation in the SNpc, determined by glial fibrillary acidic protein (GFAP) expression for astrocytes and CD11b (Mac1) expression for microglia, were detected by immunohistological staining. Correlation analysis was performed to understand the association between PDassociated behavior and pathology. The behavioral impairment progressively deteriorated during the process of experiment. In addition, the decrease in THpositive neurons was associated with an increase in GFAP and Mac1positive cells in the SNpc. Linear regression analysis indicated the association between behavioral and pathological changes. The results of the present study indicate that the APOinduced rotation, cylinder and rotarod tests are all sensitive and reliable strategies to predict the loss of TH+ neurons. These results provide a potential intervention timepoint and a comprehensive evaluation index system for assessment of PD therapeutic strategies using the hemiparkinsonian rat.
Assuntos
Hidroxidopaminas , Doença de Parkinson Secundária/patologia , Animais , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Masculino , Atividade Motora , Neurônios/patologia , Doença de Parkinson Secundária/fisiopatologia , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Substância Negra/patologia , Substância Negra/fisiopatologiaRESUMO
Parkinson's disease (PD) is a common neurodegenerative disease. The pathological hallmark of PD is a progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta in the brain, ultimately resulting in severe striatal dopamine deficiency and the development of primary motor symptoms (e.g., resting tremor, bradykinesia) in PD. Acupuncture has long been used in traditional Chinese medicine to treat PD for the control of tremor and pain. Accumulating evidence has shown that using electroacupuncture (EA) as a complementary therapy ameliorates motor symptoms of PD. However, the most appropriate timing for EA intervention and its effect on dopamine neuronal protection remain unclear. Thus, this study used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model (systemic-lesioned by intraperitoneal injection) and the 1-methyl-4-phenylpyridinium (MPPâº)-lesioned rat model (unilateral-lesioned by intra-SN infusion) of PD, to explore the therapeutic effects and mechanisms of EA at the GB34 (Yanglingquan) and LR3 (Taichong) acupoints. We found that EA increased the latency to fall from the accelerating rotarod and improved striatal dopamine levels in the MPTP studies. In the MPP⺠studies, EA inhibited apomorphine induced rotational behavior and locomotor activity, and demonstrated neuroprotective effects via the activation of survival pathways of Akt and brain-derived neurotrophic factor (BDNF) in the SN region. In conclusion, we observed that EA treatment reduces motor symptoms of PD and dopaminergic neurodegeneration in rodent models, whether EA is given as a pretreatment or after the initiation of disease symptoms. The results indicate that EA treatment may be an effective therapy for patients with PD.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Discinesias/fisiopatologia , Eletroacupuntura , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Discinesias/terapia , Eletroacupuntura/métodos , Camundongos , Atividade Motora , Doença de Parkinson/terapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/fisiopatologiaRESUMO
Dopamine replacement therapy (DRT) reduces motor symptoms in Parkinson's disease (PD), but also induces impulsive-compulsive behavior (ICB) in up to 25% of PD patients. These non-motor side effects of DRT generally follow a gradual transition from impulsive to compulsive-like-i.e. repetitive, compelled, and non-pleasurable-behavior. Here, we investigated the effect of chronic pramipexole (PPX) treatment on the onset of compulsive-like behavior, measured via the post-training signal attenuation (PTSA) procedure, in rats with dopaminergic lesions. Accordingly, we aimed to mimic chronic DRT in a PD context, and obtain data on the brain regions that potentially sustain this type of compulsive behavior pattern in rats. We observed that the lesion or treatment alone did not induce compulsive lever pressing in rats. However, rats with lesions of the substantia nigra and ventral tegmental area as well as with chronic PPX treatment developed strong compulsive lever-pressing behavior, as measured via PTSA. Furthermore, when chronic PPX treatment was discontinued before the PTSA test, the lesioned rats showed the same level of compulsive behavior as sham-operated rats. In fact, lesioned, treated, and compulsive-like rats showed significantly higher Fos expression in the orbitofrontal cortex and dorsal striatum. Thus, chronic PPX treatment in PD rats induced a strong compulsive-like behavior. Furthermore, Fos expression mapping suggests that the behavior was sustained via the activation of the orbitofrontal cortex and dorsal striatum.
Assuntos
Antiparkinsonianos/efeitos adversos , Benzotiazóis/efeitos adversos , Comportamento Compulsivo/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Animais , Antiparkinsonianos/farmacologia , Benzotiazóis/farmacologia , Comportamento Compulsivo/fisiopatologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Imuno-Histoquímica , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Oxidopamina , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Pramipexol , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/patologia , Área Tegmentar Ventral/fisiopatologiaRESUMO
Transforming growth factor-ß (TGF-ß) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-ß signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-ß signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-ß signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-ß signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENT We show that reducing Transforming growth factor-ß (TGF-ß) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-ß signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-ß signaling as a potential therapy for Parkinson's disease.
Assuntos
Intoxicação por MPTP/fisiopatologia , Neostriado/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Transdução de Sinais , Substância Negra/fisiopatologia , Fator de Crescimento Transformador beta/deficiência , Animais , Sobrevivência Celular/genética , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/fisiopatologia , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Neurodegenerativas/induzido quimicamente , Equilíbrio Postural , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genéticaRESUMO
Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+.
Assuntos
Dopamina/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Encefalite/induzido quimicamente , Ácido Hipocloroso/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , Substância Negra/efeitos dos fármacos , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Encefalite/metabolismo , Encefalite/patologia , Encefalite/fisiopatologia , Feminino , Humanos , Ácido Hipocloroso/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/fisiopatologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The diagnosis of Parkinson's disease (PD) currently relies on the appearance of certain clinical features. However, these features appear only years after the loss of nigral dopaminergic neurons. The progression of PD may be measured using clinical rating scales that are subjective and that have a variable inter-rater consistency. There is a growing need for a biomarker that will allow for early detection of the disease as well as provide a measure of disease progression. In this article, we review different biomarkers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We also discuss the use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, a combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of any interventions.