RESUMO
Gait differentiation in progressive supranuclear palsy (PSP) and vascular parkinsonism (VaP) is sometimes difficult to detect with the naked eye. Here, we compared specific gait parameters, neuro-morphometric indices, and their associations between patients with PSP Richardson's syndrome (PSP-RS) and VaP. A total of 18 PSP-RS and 13 VaP patients were recruited. Spatio-temporal gait parameters (GAITRite®) and neuroanatomical morphometry (FreeSurfer pipeline) were assessed. The groups were compared using unpaired t-tests involving 10000 random permutations after statistically controlling for total UPDRS-III and H&Y scores. Statistically significant differences between the groups were decided at < 5% Benjamini-Hochberg False Discovery Rate (FDR) for multiple-comparison related corrections. Spearman's correlations were performed to assess the significant associations (p < 0.05) between the gait parameters and morphometry indices. Among all the spatio-temporal gait parameters, PSP-RS patients displayed greater stride time, step time, swing time, and stance time variabilities compared to VaP. Morphometric analyses showed that thalamus, and caudate volumes were significantly lower, but cerebellar cortex, hippocampus, amygdala, accumbens, and putamen volumes were higher in PSP-RS than VaP. Moreover, the bilateral insula was significantly thinner in VaP than in PSP-RS. Correlation analyses support the involvement of limbic structures besides cerebellum in postural control during self-paced walking of PSP-RS patients. Our findings underline the importance of examining individual brain regions to understand the association of cortical and subcortical morphometric estimates and gait variability parameters in PSP-RS and VaP. This study suggests the involvement of the limbic system in addition to the classical neural structures for motor control and gait.
Assuntos
Doença de Parkinson Secundária , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Paralisia Supranuclear Progressiva/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Encéfalo/diagnóstico por imagem , Doença de Parkinson Secundária/complicações , MarchaRESUMO
Research suggests a possible link between chronic infection with hepatitis C virus (HCV) and the development of Parkinson's Disease (PD) and secondary Parkinsonism (PKM). We investigated the impact of antiviral treatment status (untreated, interferon [IFN] treated, direct-acting antiviral [DAA] treated) and outcome (treatment failure [TF] or sustained virological response [SVR]) on risk of PD/PKM among patients with HCV. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we applied a discrete time-to-event approach with PD/PKM as the outcome. We performed univariate followed by a multivariable modelling that used time-varying covariates, propensity scores to adjust for potential treatment selection bias and death as a competing risk. Among 17,199 confirmed HCV patients, we observed 54 incident cases of PD/PKM during a mean follow-up period of 17 years; 3753 patients died during follow-up. There was no significant association between treatment status/outcome and risk of PD/PKM. Type 2 diabetes tripled risk (hazard ratio [HR] 3.05; 95% CI 1.75-5.32; p < .0001) and presence of cirrhosis doubled risk of PD/PKM (HR 2.13, 95% CI 1.31-3.47). BMI >30 was associated with roughly 50% lower risk of PD/PKM than BMI <25 (HR 0.43; 0.22-0.84; p = .0138). After adjustment for treatment selection bias, we did not observe a significant association between HCV patients' antiviral treatment status/outcome on risk of PD/PKM. Several clinical risk factors-diabetes, cirrhosis and BMI-were associated with PD/PKM.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Doença de Parkinson Secundária , Doença de Parkinson , Humanos , Antivirais/uso terapêutico , Estudos de Coortes , Doença de Parkinson/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Hepacivirus , Resposta Viral Sustentada , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/tratamento farmacológico , Cirrose Hepática/complicações , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológicoRESUMO
BACKGROUND: Rare cases of coexisting multiple sclerosis and parkinsonism have been reported in the literature. However, the true prevalence, clinical characteristics, and causal relation between the two entities have not been systematically evaluated. OBJECTIVE: To evaluate the prevalence of parkinsonism in patients with multiple sclerosis and examine the causal relationship, if any. METHODS: Consecutive patients referred to the multiple sclerosis clinic were evaluated by a neurologist with double training in both neuroimmunology and movement disorders. All patients were specifically screened for movement disorders via a movement disorder survey and a focused exam. Video samples were independently rated by two blinded movement disorder raters. Pre-specified criteria were developed for five potential clinical scenarios: incidental idiopathic Parkinson's disease, incidental Parkinson-plus syndrome, drug-induced parkinsonism, acute symptomatic parkinsonism, and chronic symptomatic parkinsonism. RESULTS: From 2016 to 2021, 336 patients were evaluated. Of those, 12 patients (3.6%) had clinical parkinsonism (average age 68 years, 66% females). Nine patients (75%) were deemed to have incidental Parkinson's disease, 2 (17%) had drug-induced parkinsonism, and 1 (8.3%) was deemed to have demyelination-related chronic symptomatic parkinsonism. The latter presented with gradual and progressive parkinsonism without prodromal symptoms. Both blinded raters agreed with the parkinsonism phenomenology. In addition to typical enhancing and non-enhancing demyelinating lesions, the patient had lesions bilaterally in the basal ganglia. She had positive oligoclonal bands in the cerebrospinal fluid. DAT scan was normal. She was diagnosed with PPMS with activity and progression manifesting solely with secondary parkinsonism. Her disease stabilized with ocrelizumab. There were no cases of acute symptomatic parkinsonism or co-existing Parkinson-plus syndrome over the five-year duration of the study. Three of the incidental idiopathic Parkinson's disease cases had radiologically isolated syndrome. CONCLUSION: Parkinsonism in MS is rare and most cases are incidental. However, clinicians need to recognize the entity of demyelination-related chronic symptomatic parkinsonism in patients with progressive MS phenotypes and demyelinating lesions in the basal ganglia and/or upper midbrain. Parkinsonism may be the sole clinical presentation of progressive MS and the only indication for DMT initiation or escalation. There is an over-representation of radiologically isolated syndrome in patients with presumptive incidental demyelination and idiopathic Parkinson's disease. Prospective studies utilizing high-field MRI and longitudinal DAT scans are needed to better characterize the complex relationship between demyelination and parkinsonism.
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Doenças Desmielinizantes , Esclerose Múltipla , Doença de Parkinson Secundária , Doença de Parkinson , Transtornos Parkinsonianos , Doenças Desmielinizantes/complicações , Feminino , Humanos , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/epidemiologia , Doença de Parkinson/complicações , Doença de Parkinson Secundária/complicações , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/epidemiologia , Estudos Prospectivos , SíndromeRESUMO
INTRODUCTION: To delineate the determinants of motor severity in vascular parkinsonism (VaP), we investigated the impact of regional white matter intensity (WMH) burden and co-morbidities on the motor score in the patients with VaP and normal dopamine transporter (DAT) imaging. METHODS: In this multicenter, retrospective study, we reviewed the records of 63 patients diagnosed with VaP and normal DAT imaging on 18F-FP-CIT PET. Signal hyperintensities in deep white matter (DWMH), periventricular (PVH), basal ganglia (BG) regions, and infratentorial foci (ITF) were rated according to Scheltens scale, a semi-quantitative visual rating system. Motor severity was assessed with Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Regional hyperintensity scores, patients' demographics, and co-morbidities such as type 2 diabetes, hypertension, dyslipidemia, and previous stroke history were used as starting variables, and stepwise regression analysis was performed to select independent predictors of motor severity. RESULTS: PVH (R = 0.33, p = 0.008) and DWMH score (R = 0.31, p = 0.015) correlated with the motor severity, while BG and ITF scores did not. Diabetic patients had significantly higher motor scores compared with non-diabetics (34.7 (13.0) vs. 27.5 (12.4), p = 0.008). Other factors such as sex, BMI, hypertension, dyslipidemia, and previous history of stroke did not impact motor severity. In multivariate analysis, PVH scores and diabetes significantly correlated with motor severity. CONCLUSION: PVH burden and diabetes were independent factors associated with motor severity in VaP with normal DAT imaging. Our results suggest that diabetes, along with white matter hyperintensities, may have a significant role in the development of motor symptoms in VaP.
Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Doença de Parkinson Secundária , Acidente Vascular Cerebral , Substância Branca , Diabetes Mellitus Tipo 2/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson Secundária/complicações , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Substância Branca/metabolismoRESUMO
Parkinson's disease (PD) and diabetes mellitus share similar pathophysiological characteristics, genetic and environmental factors. It has been reported that people with diabetes mellitus appear to have a remarkable higher incidence of PD than age matched non diabetic individuals. Evidences suggest that use of antidiabetic glitazone is associated with a diminished risk of PD incidence in patients with diabetes. This study examined the effect of lobeglitazone, a member of thiazolidinedione class, in rat model of Parkinson's disease with diabetes co-morbidity. Rats received either rotenone and/or a combination of streptozocin and a high calorie diet for disease induction and they were treated with different doses of lobeglitazone or its vehicle. Behavioral tests comprising rotarod, bar test and rearing test were conducted to evaluate the motor function. Changes in the level tyrosine hydroxylase, TNF-α and NF-κB were analyzed using ELISA. In the same brain regions the possible changes in PPAR-γ receptor level were evaluated. Findings showed that although lobeglitazone tends to reverse the effect of rotenone in animals with diabetes, it was just able to prevent partly the motor defect in rearing test. Furthermore, lobeglitazone (1 mg/kg) reversed, in substantia nigra and striatum, the changes in tyrosine hydroxylase, TNF-α, NF-κB and PPAR-γ receptor content induced by rotenone in rats with diabetic condition. Although other preclinical studies are needed, these findings suggest that lobeglitazone is a promising neuroprotective candidate for clinical trials for PD patients with diabetes co-morbidity.
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Diabetes Mellitus Experimental/fisiopatologia , Hipoglicemiantes/farmacologia , Atividade Motora/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Doença de Parkinson Secundária/fisiopatologia , Pirimidinas/farmacologia , Tiazolidinedionas/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Masculino , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Ratos , Ratos Wistar , RotenonaRESUMO
Gut microbial dysbiosis and alteration of gut microbiota composition in Parkinson's disease (PD) have been increasingly reported, no recognized therapies are available to halt or slow progression of PD and more evidence is still needed to illustrate its causative impact on gut microbiota and PD and mechanisms for targeted mitigation. Epidemiological evidence supported an association between milk intake and a higher incidence of Parkinson's disease (PD), questions have been raised about prospective associations between dietary factors and the incidence of PD. Here, we investigated the significance of casein in the development of PD. The mice were given casein (6.75 g/kg i.g.) for 21 days after MPTP (25 mg/kg i.p. × 5 days) treatment, the motor function, dopaminergic neurons, inflammation, gut microbiota and fecal metabolites were observed. The experimental results revealed that the mice with casein gavage after MPTP treatment showed a persisted dyskinesia, the content of dopamine in striatum and the expression of TH in midbrain and ileum were decreased, the expression of Iba-1, CD4, IL-22 in midbrain and ileum increased continuously with persisted intestinal histopathology and intestinal barrier injury. Decreased intestinal bile secretion in addition with abnormal digestion and metabolism of carbohydrate, lipids and proteins were found, whereas these pathological status for the MPTP mice without casein intake had recovered after 24 days, no significant differences were observed with regard to only treated with casein. Our study demonstrates that intestinal pathologic injury, intestinal dysbacteriosis and metabolism changes promoted by casein in MPTP mice ultimately exacerbated the lesions to dopaminergic neurons.
Assuntos
Caseínas/farmacologia , Disbiose/metabolismo , Inflamação/metabolismo , Doença de Parkinson Secundária/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Caseínas/administração & dosagem , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Disbiose/induzido quimicamente , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/enzimologia , Íleo/metabolismo , Íleo/patologia , Inflamação/etiologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/enzimologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Junções Íntimas/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
AIM: To understand why autonomic failures, a common non-motor symptom of Parkinson's disease (PD), occur earlier than typical motor disorders. METHODS: Vagal application of DOPAL (3,4-dihydroxyphenylacetaldehyde) to simulate PD-like autonomic dysfunction and understand the connection between PD and cardiovascular dysfunction. Molecular and morphological approaches were employed to test the time-dependent alternation of α-synuclein aggregation and the ultrastructure changes in the heart and nodose (NG)/nucleus tractus solitarius (NTS). RESULTS: Blood pressure (BP) and baroreflex sensitivity of DOPAL-treated rats were significantly reduced accompanied with a time-dependent change in orthostatic BP, consistent with altered echocardiography and cardiomyocyte mitochondrial ultrastructure. Notably, time-dependent and collaborated changes in Mon-/Tri-α-synuclein were paralleled with morphological alternation in the NG and NTS. CONCLUSION: These all demonstrate that early autonomic dysfunction mediated by vagal application of DOPAL highly suggests the plausible etiology of PD initiated from peripheral, rather than central site. It will provide a scientific basis for the prevention and early diagnosis of PD.
Assuntos
Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Doenças do Sistema Nervoso Autônomo/patologia , Doença de Parkinson Secundária/patologia , Nervo Vago , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Animais , Doenças do Sistema Nervoso Autônomo/etiologia , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia , Hipotensão Ortostática/fisiopatologia , Masculino , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Gânglio Nodoso/patologia , Doença de Parkinson Secundária/complicações , Ratos , Ratos Sprague-Dawley , alfa-Sinucleína/biossíntese , alfa-Sinucleína/genéticaRESUMO
The hyperactivity of the lateral habenula (LHb) is closely associated with depression. At present, it is unknown how GABA transporter (GAT) in the LHb affects depressive-like behaviors, particularly in Parkinson's disease (PD)-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to sham-lesioned rats. Intra-LHb injection of GAT-1 inhibitor NO-711 produced antidepressant-like responses, decreased firing rate of LHb neurons, and increased levels of LHb extracellular GABA in sham-lesioned and the lesioned rats. Further, the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the lesioned rats, the duration of inhibitory effect on the firing rate and increased levels of the GABA induced by NO-711 was longer than those in sham-lesioned rats, respectively. Intra-LHb injection of GAT-3 inhibitor SNAP-5114 improved depressive-like behaviors and decreased firing rate of LHb neurons in the lesioned rats, but not in sham-lesioned rats. SNAP-5114 increased LHb GABA levels in the lesioned rats, whereas did not alter that in sham-lesioned rats. These changes were involved in the down-regulated expression of LHb GAT-1 and GAT-3 after lesioning the SNc. These findings suggest that GAT-1 plays a major role in transporting LHb GABA under physiological conditions, and depletion of dopamine increases the transport capacity of GAT-3 in the LHb. Further, the study provides evidence that GAT-1 and GAT-3 in the LHb are involved in the regulation of PD-related depression.
Assuntos
Depressão/tratamento farmacológico , Depressão/psicologia , Antagonistas GABAérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA/efeitos dos fármacos , Habenula/efeitos dos fármacos , Doença de Parkinson Secundária/psicologia , Animais , Anisóis/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/etiologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos , Hidroxidopaminas , Masculino , Ácidos Nipecóticos/farmacologia , Oximas/farmacologia , Doença de Parkinson Secundária/complicações , Ratos , Ratos Sprague-Dawley , Natação/psicologia , Ácido gama-Aminobutírico/metabolismoRESUMO
BACKGROUND: Gastrointestinal (GI) dysfunction, including constipation, is a common non-motor symptom of Parkinson's disease (PD). The toxin 6-hydroxydopamine (6OHDA) produces the symptoms of PD, surprisingly including constipation, after it is injected into the medial forebrain bundle (MFB). However, the mechanisms involved in PD-associated constipation caused by central application of 6OHDA remain unknown. We investigated effects of 6OHDA lesioning of the MFB on motor performance and GI function. METHODS: Male Sprague Dawley rats were unilaterally injected with 6OHDA in the MFB. Colorectal propulsion was assessed by bead expulsion after 4 weeks and by recording colorectal contractions and propulsion after 5 weeks. Enteric nervous system (ENS) neuropathy was examined by immunohistochemistry. KEY RESULTS: When compared to shams, 6OHDA-lesioned rats had significantly increased times of bead expulsion from the colorectum, indicative of colon dysmotility. Administration of the colokinetic, capromorelin, that stimulates defecation centers in the spinal cord, increased the number of contractions and colorectal propulsion in both groups compared to baseline; however, the effectiveness of capromorelin in 6OHDA-lesioned rats was significantly reduced in comparison with shams, indicating that 6OHDA animals have reduced responsiveness of the spinal defecation centers. Enteric neuropathy was observed in the distal colon, revealing that lesion of the MFB has downstream effects at the cellular level, remote from the site of 6OHDA administration. CONCLUSIONS & INFERENCES: We conclude that there are trans-synaptic effects of the proximal, forebrain, lesion of pathways from the brain that send signals down the spinal cord, at the levels of the defecation centers and the ENS.
Assuntos
Constipação Intestinal/fisiopatologia , Corpo Estriado/fisiopatologia , Neurônios Dopaminérgicos/fisiologia , Motilidade Gastrointestinal/fisiologia , Doença de Parkinson Secundária/fisiopatologia , Substância Negra/fisiopatologia , Animais , Constipação Intestinal/etiologia , Masculino , Doença de Parkinson Secundária/complicações , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: We aimed to characterize parkinsonian features and gait performance of psychiatric patients on neuroleptics (PPN) and to compare them to Parkinson's disease (PD) and healthy controls (HC). METHODS: Hospitalized PPN (n = 27) were recruited, examined, and rated for parkinsonian signs according to the motor part of the Movement Disorders Society Unified Parkinson's Disease Rating Scale and performed a 10-m "timed-up-and-go" (TUG) test with a smartphone-based motion capture system attached to their sternum. Gait parameters and mUPDRS scores were compared to those of consecutive age-matched PD patients (n = 18) and HC (n = 27). RESULTS: Psychiatric patients on neuroleptics exhibited parkinsonism (mUPDRS score range: 8-44) but less than that of PD patients (18.2 ± 9.2 vs 29.8 ± 10.3, P = 0.001). TUG times were slower for PPN and PD versus HC (total: 30.6 ± 7.6 seconds vs 30.0 ± 7.3 seconds vs 20.0 ± 3.2 seconds, straight walking: 10.6 ± 2.7 seconds vs 10.6 ± 2.4 seconds vs 6.8 ± 1.2 seconds) (P < 0.001), and cadence and step length were similar among PPN and PD and different from HC as well. Although their gait speed was slower than HC but similar to PD, PPN had lower mediolateral sway (4.3 ± 1.1 cm vs 6.7 ± 2.9 cm vs 6.9 ± 2.9 cm, respectively, P < 0.001) than both. CONCLUSIONS: Parkinsonism is very common in hospitalized PPN, but usually milder than that of PD. It seems that wearable sensor-based technology for assessing gait and balance may present a more sensitive and quantitative tool to detect clinical aspects of neuroleptic-induced parkinsonism than standard clinical ratings.
Assuntos
Antipsicóticos/efeitos adversos , Análise da Marcha/estatística & dados numéricos , Transtornos Mentais/complicações , Transtornos Mentais/fisiopatologia , Doença de Parkinson Secundária/fisiopatologia , Doença de Parkinson/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Feminino , Análise da Marcha/métodos , Humanos , Pacientes Internados , Masculino , Transtornos Mentais/tratamento farmacológico , Pessoa de Meia-Idade , Monitorização Ambulatorial/métodos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Adulto JovemRESUMO
There is growing awareness within the scientific community of the strong connection between the inflammation in the intestine and the pathogenesis of Parkinson's disease (PD). In previous studies we developed a PD animal model exposing pup rats to permethrin (PERM) pesticide. Here, we intended to explore whether in our animal model there were changes in gut permeability, fecal microbiota and hepatic injury. Moreover, we tested if the co-treatment with an electrolyzed reduced (ERW) was effective to protect against alterations induced by PERM. Rats (from postnatal day 6 to 21) were gavaged daily with PERM, PERM+ERW or vehicle and gut, liver and feces were analyzed in 2-months-old rats. Increased gut permeability, measured by FITC-dextran assay, was detected in PERM group compared to control and PERM+ERW groups. In duodenum and ileum, concentration of occludin was higher in control group than those measured in PERM group, whereas only in duodenum ZO-1 was higher in control than those measured in PERM and PERM+ERW groups. Number of inflammatory focis and neutrophils as well as iNOS protein levels were higher in livers of PERM-treated rats than in those of PERM+ERW and control rats. Fecal microbiota analysis revealed that Lachnospira was less abundant and Defluviitaleaceae more abundant in the PERM group, whereas the co-treatment with ERW was protective against PERM treatment since the abundances in Lachnospira and Defluviitaleaceae were similar to those in the control group. Higher abundances of butyrate- producing bacteria such as Blautia, U.m. of Lachnospiraceae family, U.m. of Ruminococcaceae family, Papillibacter, Roseburia, Intestinimonas, Shuttleworthia together with higher butyric acid levels were detected in PERM+ERW group compared to the other groups. In conclusion, the PD animal model showed increased intestinal permeability together with hepatic inflammation correlated with altered gut microbiota. The positive effects of ERW co-treatment observed in gut, liver and brain of rats were linked to changes on gut microbiota.
Assuntos
Inflamação/tratamento farmacológico , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Água/administração & dosagem , Animais , Eletrólise , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/microbiologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Doença de Parkinson/complicações , Doença de Parkinson/microbiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/microbiologia , Permeabilidade/efeitos dos fármacos , Permetrina/toxicidade , Ratos , Água/químicaRESUMO
AIM: Modulation of electrical activity in the subthalamic nucleus has been therapeutically effective in Parkinson's disease. Pharmacological manipulation of glutamate release from subthalamic neurons could also favourably alter basal ganglia activity to improve motor symptoms. This study investigates the efficacy of selective suppression of hyperactive glutamatergic input from the subthalamic nucleus to the globus pallidus internal segment by botulinum toxin A (BoNT-A) in a parkinsonian model. METHODS: Unilateral 6-hydroxydopamine lesioned parkinsonian rodents and controls received microinfusions of BoNT-A or vehicle into the ipsilateral internal globus pallidus (n = 8 per group). Changes in gait were measured by the CatWalk apparatus, along with assessment of apomorphine-induced rotational behaviour prior to and following BoNT-A injection. Immunofluorescent staining for markers of glutamatergic, GABAergic and total terminals was performed at the internal globus pallidus. RESULTS: Administration of a single dose of BoNT-A (0.5 ng) significantly improved the rotational asymmetry and gait abnormalities. Ameliorations in speed, body speed variation, cadence and walking pattern were comparable to pre-lesioned animals, and persisted up to 1 month following BoNT-A injection. These changes are associated to BoNT-A's ability to selectively target glutamatergic terminals. CONCLUSION: Blockade of subthalamic hyperactivity by BoNT-A leads to sufficient reorganization in the basal ganglia needed to generate a consistent rhythmic pattern of walking. This suggests the potential use of intracerebral BoNT-A to produce effective neuromodulation in the parkinsonian brain, as well as expansion into other neurodegenerative disorders linked to excitotoxity.
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Toxinas Botulínicas Tipo A/farmacologia , Transtornos Neurológicos da Marcha/tratamento farmacológico , Doença de Parkinson Secundária/complicações , Animais , Toxinas Botulínicas Tipo A/administração & dosagem , Núcleo Entopeduncular/efeitos dos fármacos , Transtornos Neurológicos da Marcha/etiologia , Oxidopamina/toxicidade , RatosRESUMO
The development of Parkinson's disease (PD) involves the degeneration of dopaminergic neurons caused by oxidative stress. Accumulating clinical evidence indicates that high blood levels of uric acid (UA), an intrinsic antioxidative substance, are associated with reduced risk of PD. However, this hypothesis has not been confirmed by in-vivo experiments. The present study investigated the effects of UA on behavioral abnormalities in the development of PD. We used unilateral 6-hydroxydopamine-lesioned mice, which were fed on a diet containing 1% UA and 2.5% potassium oxonate (an uricase inhibitor) to induce hyperuricemia. A significant elevation in UA levels was found in groups that were fed a UA diet. The 6-hydroxydopamine-lesioned mice showed impaired rotarod performance and increased apomorphine-induced contralateral rotations. These behavioral abnormalities were significantly reversed by feeding a UA diet for 1 week before and 5 weeks after surgery (subchronic hyperuricemia). These behavioral improvements occurred in parallel with recovery of tyrosine hydroxylase protein levels in the lesioned striatal side. The present study with a dietary hyperuricemia mice model confirms that UA exerts a neuroprotective effect on dopaminergic neuronal loss, improving motor dysfunction and ameliorating PD development.
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Transtornos Mentais/sangue , Transtornos Mentais/etiologia , Doença de Parkinson Secundária/complicações , Ácido Úrico/sangue , Adrenérgicos/toxicidade , Animais , Apomorfina/farmacologia , Modelos Animais de Doenças , Hiperuricemia/sangue , Hiperuricemia/etiologia , Masculino , Transtornos Mentais/dietoterapia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Oxidopamina/toxicidade , Ácido Oxônico/administração & dosagem , Doença de Parkinson Secundária/induzido quimicamente , Teste de Desempenho do Rota-Rod , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
BACKGROUND: In Parkinson's disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with inflammation. Nucleotide-binding oligomerization domain-containing protein (NOD)2, one of the first discovered NOD-like receptors, plays an important role in inflammation. However, the role of NOD2 has not been elucidated in PD. METHODS: NOD2 mRNA and protein expression in the SN and the striatum of C57BL/6 mice treated with 6-hydroxydopamine (6-OHDA) was measured. We next investigated the potential contribution of the NOD2-dependent pathway to 6-OHDA-induced DA degeneration using NOD2-deficient (NOD2-/-) mice. Assays examining DA degeneration and inflammation include HPLC, Western blot, immunohistochemistry, TUNEL staining, and cytometric bead array. To further explore a possible link between NADPH oxidase 2 (NOX2) and NOD2 signaling in PD, microglia were transfected with shRNA specific to NOX2 in vitro and apocynin were given to mice subjected to 6-OHDA and muramyl dipeptide (MDP) striatal injection. RESULTS: The expression of NOD2 was upregulated in an experimental PD model induced by the neurotoxin 6-OHDA. NOD2 deficiency resulted in a protective effect against 6-OHDA-induced DA degeneration and neuronal death, which was associated with the attenuated inflammatory response. Moreover, silencing of NOX2 in microglia suppressed the expression of NOD2 and the inflammatory response induced by 6-OHDA and attenuated the toxicity of conditioned medium from 6-OHDA or MDP-stimulated microglia to neuronal cells. Furthermore, apocynin treatment inhibited NOD2 upregulation and DA degeneration in the SN of WT mice induced by 6-OHDA and MDP. CONCLUSION: This study provides the direct evidence that NOD2 is related to 6-OHDA-induced DA degeneration through NOX2-mediated oxidative stress, indicating NOD2 is a novel innate immune signaling molecule participating in PD inflammatory response.
Assuntos
Dopamina/metabolismo , Regulação da Expressão Gênica/genética , NADPH Oxidase 2/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Acetofenonas/farmacologia , Acetofenonas/uso terapêutico , Animais , Apomorfina/farmacologia , Linhagem Celular Transformada , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/genética , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative disorder accompanied by movement deficits with selective degeneration of dopaminergic neurons in the substantia nigra (SN). Recent studies indicate that early diagnosis of PD has important implications for the disease-modifying strategy for PD showing not only some dopaminergic neuronal damage but also non-motor symptoms, which occur several years before the onset of motor symptoms. However, studies on the relationship between non-motor symptoms and its underlying mechanisms from the early to the late phase of PD are unknown. Here, we aimed to show alterations in the non-motor symptoms of PD, including colonic dysmotility and impaired olfaction, and the related factors by intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) plus probenecid (MPTP/p). A mouse model of the early stage of PD was developed by systemic administration of MPTP (25â¯mg/kg, i.p.) and probenecid (100â¯mg/kg, i.p.) at 3.5-day intervals for a total of 10 injections. We performed motor and non-motor behavioral tests after 3 (called asymptomatic) and 10 (called symptomatic) injections of MPTP/p compared with the untreated (called control) group. We found that there were motor disturbances at the symptomatic stage, while impairments in intestinal motility and olfaction were observed from the asymptomatic stage. We also found the reduction of dopaminergic neuronal cell numbers in the SN and striatal dopamine transporter levels starting from the asymptomatic stage. At both asymptomatic and symptomatic stages, we demonstrated alterations in the expression of several proteins that are associated with non-motor deficits in the mouse ileum or olfactory bulb compared with the control group. Our findings in chronic MPTP/p-induced mice suggest their potential use as an animal model for the early stage of PD as well as a significant correlation between changes in relevant factors and symptoms.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Gastroenteropatias/induzido quimicamente , Motilidade Gastrointestinal/efeitos dos fármacos , Neurotoxinas/toxicidade , Transtornos do Olfato/induzido quimicamente , Probenecid/toxicidade , Animais , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Transtornos do Olfato/diagnóstico , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
OBJECTIVE: Augmentation with aripiprazole is an effective pharmacotherapy for treatment-resistant late-life depression (LLD). However, aripiprazole can cause extrapyramidal symptoms (EPS) such as akathisia and parkinsonism; these symptoms are distressing and can contribute to treatment discontinuation. We investigated the clinical trajectories and predictors of akathisia and parkinsonism in older patients receiving aripiprazole augmentation for treatment-resistant LLD. METHODS: Between 2009 and 2013, depressed older adults who did not remit with venlafaxine were randomized to aripiprazole or placebo in a 12-week trial. Participants were 60 years or older and met DSM-IV-TR criteria for major depressive episode with at least moderate symptoms. The presence of akathisia and parkinsonism was measured at each visit using the Barnes Akathisia Scale (BAS) and Simpson-Angus Scale (SAS), respectively. In an exploratory analysis, we examined a broad set of potential clinical predictors and correlates: age, sex, ethnicity, weight, medical comorbidity, baseline anxiety severity, depression severity, concomitant medications including rescue medications, and aripiprazole dosage. RESULTS: Twenty-four (26.7%) of 90 participants randomized to aripiprazole and who had akathisia scores available developed akathisia compared to 11 (12.2%) of 90 randomized to placebo. Greater depression severity was the main predictor of treatment-emergent akathisia. Most participants who developed akathisia improved over time, especially with reductions in dosage. Fifteen (16.5%) of 91 participants taking aripiprazole and who had parkinsonism scores available developed parkinsonism, but no clinical predictors or correlates were identified. CONCLUSIONS: Akathisia is a common side effect of aripiprazole, but it is typically mild and responds to dose reduction. Patients with greater baseline depression may warrant closer monitoring for akathisia. More research is needed to understand the course and predictors of treatment-emergent EPS with antipsychotic augmentation for treatment-resistant LLD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00892047.
Assuntos
Antidepressivos/efeitos adversos , Aripiprazol/efeitos adversos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtornos de Início Tardio/tratamento farmacológico , Idoso , Acatisia Induzida por Medicamentos/complicações , Antidepressivos/uso terapêutico , Aripiprazol/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/complicações , Feminino , Humanos , Transtornos de Início Tardio/complicações , Masculino , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Pain is a major non motor symptom that contributes to impaired quality of life in PD. However, its mechanism is unknown. OBJECTIVES AND METHODS: We sought to identify the pain phenotypes and parallel changes in spinal integration of peripheral stimuli in a rat model of PD induced by lesions of SN dopamine neurons, using behavioral plantar and von Frey tests as well as electrophysiology of the dorsal horn. RESULTS: We show that dopamine depletion by 6-OHDA induced hypersensitivity to mechanical and thermal stimuli. These abnormal behaviors were paralleled by increased neuronal responses and hyperexcitability of wide dynamic range neurons of lamina V of the dorsal horn of the spinal cord in response to electrical stimulation of the sciatic nerve in the 6-OHDA model as compared to sham rats. CONCLUSIONS: These results provide evidence for alteration of nociceptive integration in the spinal dorsal horn neurons in 6-OHDA rats that can reflect changes in pain behavior. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Hiperalgesia/etiologia , Hipercinese/induzido quimicamente , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/patologia , Medula Espinal/patologia , Potenciais de Ação/fisiologia , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Lateralidade Funcional , Hiperalgesia/patologia , Masculino , Neurônios/fisiologia , Oxidopamina/toxicidade , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Doença de Parkinson Secundária/induzido quimicamente , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Simpatolíticos/toxicidadeRESUMO
While people are often aware of the motor symptoms in Parkinson's disease (PD), few know of the many non-motor symptoms, which patients report have a greater impact on their quality of life. Gastrointestinal (GI) dysfunction is one of the most common non-motor symptoms, which can occur at any stage of PD, even years prior to diagnosis, and can affect all sections along the GI tract causing a range of symptoms including drooling, gastroparesis and constipation. We have investigated whether a neurotoxin model of PD induced by rotenone, a mitochondrial complex I inhibitor, is capable of reproducing the GI dysfunction seen clinically. Sprague-Dawley rats were administered 2.75â¯mg/kg rotenone, 5 days/week for 4 weeks, via intraperitoneal injection. Rats underwent behavioural testing, including the one-hour stool and gastric emptying tests before GI contents and tissues were collected for microbiota and histological analysis. Rats exposed to rotenone had more days with evidence of diarrhoea and significantly delayed gastric emptying, reproducing the clinical symptom of gastroparesis. Microbiota analysis revealed alterations in the small intestine and colon of rotenone-treated rats, relatively consistent with changes described in PD patients. Histological analysis demonstrated mucosal thickening and goblet cell hyperplasia in the colon of rotenone rats, which may be an adaptive response to the toxin or changes in GI microbiota. Our results indicate that rotenone may be a good model for investigating the mechanisms involved with Parkinson's GI symptoms and for screening potential therapeutic options as it is capable of recapitulating some key GI changes that occur during PD progression.
Assuntos
Colo/efeitos dos fármacos , Colo/patologia , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/microbiologia , Microbiota/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/microbiologia , Rotenona/toxicidade , Animais , Diarreia/induzido quimicamente , Diarreia/complicações , Modelos Animais de Doenças , Esvaziamento Gástrico/efeitos dos fármacos , Gastroenteropatias/complicações , Gastroenteropatias/patologia , Masculino , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/patologia , Ratos , Teste de Desempenho do Rota-RodRESUMO
The clinical features of parkinsonism in carbon monoxide (CO) intoxication have been associated with striatal-related neuronal networks. As parkinsonian and neuropsychiatric features are both related to presynaptic dopaminergic integrity, the aim of this study was to explore the clinical significance of 99mTcTRODAT-1 in grading neurobehavioral scores and parkinsonian severity in CO intoxication. We enrolled 64 patients with CO intoxication, including 29 with parkinsonism (parkinsonism[+] group) and 35 without (parkinsonism[-] group). All of the patients received 99mTcTRODAT-1 neuroimaging evaluations, comprehensive neurobehavioral tests and assessments of the severity of parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS)-part III motor score. Univariate and multivariate regression analyses were used to test the predictive factors and scores for a diagnosis of parkinsonism and its severity. The parkinsonism(+) group had significantly lower cognitive scores and higher neuropsychiatric total scores compared with the parkinsonism(-) group, both of which were independently related to the severity of parkinsonism. 99mTcTRODAT-1 regional caudate signals were correlated with tremors at rest, action or postural tremors of the hands, bradykinesia and hypokinesia, and visuospatial, verbal fluency, abstract thinking and digit backwards scores. Scores of the neurobehavioral tests and UPDRS items were highly correlated (p<0.01). Our results validated the initial hypothesis in that neurobehavioral deficits and parkinsonian symptoms were highly related. This association was independent of demographic factors and initial carboxyhemoglobin level. Within the presynaptic dopaminergic circuit, the clinical role of the caudate in mediating the clinical symptoms in CO intoxication may outweigh the putamen.
Assuntos
Intoxicação por Monóxido de Carbono/diagnóstico por imagem , Intoxicação por Monóxido de Carbono/patologia , Núcleo Caudado/metabolismo , Núcleo Caudado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Valor Preditivo dos Testes , Adulto , Intoxicação por Monóxido de Carbono/complicações , Carboxihemoglobina/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Masculino , Neuroimagem , Testes Neuropsicológicos , Compostos de Organotecnécio/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/diagnóstico por imagem , Doença de Parkinson Secundária/patologia , Índice de Gravidade de Doença , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/metabolismo , Adulto JovemRESUMO
Rotenone (organic pesticide and inhibitor of mitochondrial complex I) is used to generate an experimental model of Parkinson's disease (PD). In the present study, we investigated rotenone-induced locomotor deficits, gait dynamics and muscular weakness in rats. The study also determined dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels following rotenone administration. In the study, adult male rats were administered subcutaneously (s.c.) with rotenone (1.5 mg/kg/day) for 8 days. Motor activities were monitored by the Kondziela's inverted screen test, beam walking test and footprint test. Animals were decapitated after behavioral analysis and brains were dissected out for neurochemical estimation. Results showed that the levels of DA and DOPAC were significantly decreased, which further supported by significant impaired motor coordination in rotenone treated rats. In conclusion, the behavioral and neurochemical findings of our study further strengthen the previous report and emphasizes on short term administration of rotenone producing PD-like symptoms in rats.