RESUMO
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. Although PD etiology is not fully understood, alpha (α)-synuclein is a key protein involved in PD pathology. MicroRNAs (miRNA), small gene regulatory RNAs that control gene expression, have been identified as biomarkers and potential therapeutic targets for brain diseases, including PD. In particular, miR-124 is downregulated in the plasma and brain samples of PD patients. Recently we showed that the brain delivery of miR-124 counteracts 6-hydroxydopamine-induced motor deficits. However, its role in α-synuclein pathology has never been addressed. Here we used paraquat (PQ)-induced rat PD model to evaluate the role of miR-124-3p in α-synuclein accumulation and dopaminergic neuroprotection. Our results showed that an intranigral administration of miR-124-3p reduced the expression and aggregation of α-synuclein in the substantia nigra (SN) of rats exposed to PQ. NADPH oxidases (NOX), responsible for reactive oxygen species generation, have been considered major players in the development of α-synuclein pathology. Accordingly, miR-124-3p decreased protein expression levels of NOX1 and its activator, small GTPase Rac1, in the SN of PQ-lesioned rats. Moreover, miR-124-3p was able to counteract the reduced levels of pituitary homeobox 3 (PITX3), a protein required for the dopaminergic phenotype, induced by PQ in the SN. This is the first study showing that miR-124-3p decreases PQ-induced α-synuclein levels and the associated NOX1/Rac1 signaling pathway, and impacts PITX3 protein levels, supporting the potential of miR-124-3p as a disease-modifying agent for PD and related α-synucleinopathies.
Assuntos
MicroRNAs , Paraquat , alfa-Sinucleína , Animais , MicroRNAs/metabolismo , alfa-Sinucleína/metabolismo , Paraquat/toxicidade , Masculino , Ratos , Ratos Wistar , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Modelos Animais de Doenças , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Ratos Sprague-DawleyRESUMO
Nervonic acid (NA) is a primary long-chain fatty acid and has been confirmed to have neuroprotective effects in neurologic diseases. Oxidative stress and neuronal damage are the main causes of Parkinson's disease (PD). This study mainly explored whether NA is involved in regulating oxidative stress and apoptosis in MPTP-induced mouse model and MPP-induced cell model. Through behavior tests, we proved that MPTP-induced motor dysfunction in mice was recovered by NA treatment. NA can reduce MPTP-induced neuronal damage, manifested by elevated levels of TH and dopamine, as well as decreased levels of α-syn. In the in vitro model, we observed from CCK8 assay and flow cytometry that the induction of MPP markedly suppressed cell activity and enhanced cell apoptosis, but these functions were all reversed by NA. Furthermore, NA administration reversed the increase in ROS production and MDA levels induced by MPTP or MPP, as well as the decrease in SOD levels, suggesting the antioxidant properties of NA in PD. Meanwhile, we confirmed that NA can regulate oxidative stress and neuronal damage by activating the MEK/ERK pathway. Overall, we concluded that NA could alleviate MPTP-induced PD via MEK/ERK pathway.
Assuntos
Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Animais , Masculino , Camundongos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos Monoinsaturados/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Parkinson's disease (PD) is a chronic neurodegenerative case. As the disease progresses, the response time to doses of levodopa (L-Dopa) becomes shorter and the effects of the drug are severely limited by some undesirable side effects such as the 'on-off' phenomenon. In several diseases, including Parkinson's, nanoparticles can deliver antioxidant compounds that reduce oxidative stress. This study evaluates and compares the neuroprotective effects of L-Dopa-modified zinc nanoparticles (ZnNPs) in the 6-hydroxydopamine (6-OHDA)-induced PD rat model. For this purpose, the synthesis of NPs was carried out. Scanning electron microscopy, X-ray diffraction and Fourier transform infrared spectrophotometer were used for characterization. The rats were randomized into 9 experimental groups: control, lesion group (6-OHDA), 6-OHDA + 5 mg/kg L-Dopa, 6-OHDA + 10 mg/kg L-Dopa, 6-OHDA + 20 mg/kg L-Dopa, 6-OHDA + 20 mg/kg ZnNPs, 6-OHDA + 40 mg/kg ZnNPs, 6-OHDA + 30 mg/kg ZnNPs + L-Dopa, and 6-OHDA + 60 mg/kg ZnNPs + L-Dopa. Behavioral tests were performed on all groups 14 days after treatment. Phosphatase and tensin homolog, Excitatory amino acid transporter 1/2, and Glutamine synthetase gene analyses were performed on brain samples taken immediately after the tests. In addition, histological and immunohistochemical methods were used to determine the general structure and properties of the tissues. We obtained important findings that L-Dopa-modified ZnNPs increased the activity of glutamate transporters. Our experiment showed that glutamate increases neuronal cell vitality and improves behavioral performance. Therefore, L-Dopa-modified ZnNPs can be used to prevent neurotoxicity. According to what we found, results show that L-Dopa-modified ZnNPs will lend to the effective avoidance and therapy of PD.
Assuntos
Modelos Animais de Doenças , Levodopa , Fármacos Neuroprotetores , Oxidopamina , Óxido de Zinco , Animais , Levodopa/farmacologia , Ratos , Fármacos Neuroprotetores/farmacologia , Óxido de Zinco/química , Óxido de Zinco/farmacologia , Masculino , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Nanopartículas Metálicas/química , Nanopartículas/química , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos WistarRESUMO
In this study, the antiparkinson effect of khellin (KL) on rotenone-induced Parkinson's disease (PD) was examined in zebrafish. Initially, In silico evaluations, such as drug likeness and ADME/T analysis, confirmed the pharmacological viability of KL. Molecular docking and molecular dynamics (MD) analysis revealed stable binding interactions between KL and monamine oxidase B (MAO-B). Molecular docking results for KL and pioglitazone (CCl) revealed binding energies of -6.5 and -10.4 kcal/mol, respectively. Later, molecular dynamics (MD) studies were performed to assess the stability of these complexes, which yielded binding energies of -36.04 ± 55.21 and -56.2 ± 80.63 kJ/mol for KL and CCl, respectively. These results suggest that KL exhibits considerable binding affinity for MAO-B. In In vitro studies, according to the DPPH free radical scavenging assay, KL exhibited significant antioxidant effects, indicating that it can promote redox balance with an IC50 value of 22.68 ± 0.5 µg/ml. In vivo studies and evaluation of locomotor activity, social interaction, histopathology and biochemical parameters were conducted in KL-treated zebrafish to measure SOD and GSH antioxidant activity, the oxidative stress marker malondialdehyde (MDA), the inflammatory marker myeloperoxidase (MPO) and MAO-B. However, while the locomotor and social interaction abilities of the rotenone-treated zebrafish were significantly reduced, KL treatment significantly improved locomotor activity (p < 0.001) and social interaction (p < 0.001). KL alleviated PD symptoms, as indicated by significant increases in SOD (p < 0.01), GSH (p < 0.001), MDA (p < 0.001), MAO-B (p < 0.001) and MPO (p < 0.001) in rotenone-induced PD fish (p<0.001) significantly reduced activities. Histopathological studies revealed that rotenone-induced brain hyperintensity and abnormal cellularity of the periventricular gray matter in the optic tectum were significantly reduced by KL treatment. This study provides a strong basis for developing KL as a new candidate for the treatment of Parkinson's disease, with the prospect of improved safety profiles and efficacy.
Assuntos
Antiparkinsonianos , Simulação de Acoplamento Molecular , Monoaminoxidase , Estresse Oxidativo , Rotenona , Peixe-Zebra , Animais , Rotenona/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antiparkinsonianos/farmacologia , Monoaminoxidase/metabolismo , Simulação de Dinâmica Molecular , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Modelos Animais de Doenças , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , MasculinoRESUMO
Microglial activation contributes to the neuropathology of Parkinson's disease (PD). Inhibiting M1 while simultaneously boosting M2 microglia activation may therefore be a potential treatment for PD. Apilarnil (API) is a bee product produced from drone larvae. Recent research has demonstrated the protective effects of API on multiple body systems. Nevertheless, its impact on PD or the microglial M1/M2 pathway has not yet been investigated. Thus, we intended to evaluate the dose-dependent effects of API in rotenone (ROT)-induced PD rat model and explore the role of M1/M2 in mediating its effect. Seventy-two Wistar rats were equally grouped as; control, API, ROT, and groups in which API (200, 400, and 800 mg/kg, p.o.) was given simultaneously with ROT (2 mg/kg, s.c.) for 28 days. The high dose of API (800 mg/kg) showed enhanced motor function, higher expression of tyrosine hydroxylase and dopamine levels, less dopamine turnover and α-synuclein expression, and a better histopathological picture when compared to the ROT group and the lower two doses. API's high dose exerted its neuroprotective effects through abridging the M1 microglial activity, illustrated in the reduced expression of miR-155, Iba-1, CD36, CXCL10, and other pro-inflammatory markers' levels. Inversely, API high dose enhanced M2 microglial activity, witnessed in the elevated expression of miR-124, CD206, Ym1, Fizz1, arginase-1, and other anti-inflammatory indices, in comparison to the diseased group. To conclude, our study revealed a novel neuroprotective impact for API against experimentally induced PD, where the high dose showed the highest protection via rebalancing M1/M2 polarization.
Assuntos
MicroRNAs , Microglia , Fármacos Neuroprotetores , Ratos Wistar , Rotenona , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Masculino , Ratos , Modelos Animais de Doenças , Dopamina/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
Vascular Parkinsonism (VP) is clinical term represents a progressive ischemic changes and subcortical lacunar infarct leading to Parkinsonism mainly in the lower limbs so called lower body Parkinsonism. The VP neuropathology is differed from that of PD neuropathology which rarely associated with basal ganglion lesions. Dopamine transporters are normal in VP but are highly reduced in PD, and dopaminergic agonists had no effective role on VP. The neuropathological mechanisms of VP are related to vascular injury which induces the interruption of the neural connection between basal ganglion and cerebral cortex. Hyperlipidemia and other cardiometabolic risk factors augment VP risk and the related neuropathology. Targeting of these cardiometabolic disorders by lipid-lowering statins may be effective in the management of VP. Therefore, this mini-review aims to clarify the possible role of statins in the management of VP. Statins have neuroprotective effects against different neurodegenerative diseases by anti-inflammatory, antioxidant and antithrombotic effects with enhancement of endothelial function. In conclusion, statins can prevent and treat VP by inhibiting inflammatory and oxidative stress disorders, mitigating of white matter hyperintensities and improving of neuronal signaling pathways. Additional preclinical, clinical trials and prospective studies are warranted in this regard.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Doenças Vasculares , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/patologiaRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.
Assuntos
Mitocôndrias , Estresse Oxidativo , Ratos Sprague-Dawley , Canais de Cátion TRPC , alfa-Sinucleína , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Animais , Ratos , Estresse Oxidativo/efeitos dos fármacos , Humanos , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Linhagem Celular Tumoral , Masculino , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológicoRESUMO
Parkinson's disease is a progressive neurodegenerative disorder marked by the death of dopaminergic neurons in the substantia nigra region of the brain. Aggregation of alpha-synuclein (α-synuclein) is a contributing factor to Parkinson's disease pathogenesis. The objective of this study is to investigate the neuroprotective effects of gut microbes on α-synuclein aggregation using both in silico and in vivo approaches. We focussed on the interaction between α-synuclein and metabolites released by gut bacteria that protect from PD. We employed three probiotic microbe strains against α-synuclein protein: Lactobacillus casei, Escherichia coli, and Bacillus subtilis, with their chosen PDB IDs being Dihydrofolate reductase (3DFR), methionine synthetase (6BM5), and tryptophanyl-tRNA synthetase (3PRH), respectively. Using HEX Dock 6.0 software, we examined the interactions between these proteins. Among the various metabolites, methionine synthetase produced by E. coli showed potential interactions with α-synuclein. To further evaluate the neuroprotective benefits of E. coli, an in vivo investigation was performed using a rotenone-induced Parkinsonian mouse model. The motor function of the animals was assessed through behavioural tests, and oxidative stress and neurotransmitter levels were also examined. The results demonstrated that, compared to the rotenone-induced PD mouse model, the rate of neurodegeneration was considerably reduced in mice treated with E. coli. Additionally, histopathological studies provided evidence of the neuroprotective effects of E. coli. In conclusion, this study lays the groundwork for future research, suggesting that gut bacteria may serve as potential therapeutic agents in the development of medications to treat Parkinson's disease. fig. 1.
Assuntos
Bacillus subtilis , Escherichia coli , Microbioma Gastrointestinal , Simulação de Acoplamento Molecular , Estresse Oxidativo , Probióticos , Rotenona , alfa-Sinucleína , Animais , Camundongos , Microbioma Gastrointestinal/fisiologia , Probióticos/uso terapêutico , Probióticos/farmacologia , alfa-Sinucleína/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Rotenona/toxicidade , Lacticaseibacillus casei/fisiologia , Metionina tRNA Ligase , Triptofano-tRNA Ligase/fisiologia , Masculino , Tetra-Hidrofolato Desidrogenase/metabolismo , Simulação por Computador , Transtornos Parkinsonianos/microbiologia , Humanos , Fármacos Neuroprotetores/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Doença de Parkinson Secundária/induzido quimicamente , Neurônios Dopaminérgicos/efeitos dos fármacos , Doença de Parkinson/microbiologiaRESUMO
Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.
Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.
Assuntos
Animais , Masculino , Camundongos , Doença de Parkinson Secundária/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Antiparkinsonianos/uso terapêutico , Doença de Parkinson Secundária/induzido quimicamente , Reserpina/administração & dosagem , Carbidopa/administração & dosagem , Catalepsia/induzido quimicamente , Levodopa/administração & dosagem , Cumarínicos , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Haloperidol , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos ICR , Inibidores da Monoaminoxidase/administração & dosagem , Antiparkinsonianos/administração & dosagemRESUMO
PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 μg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 μg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta.
Assuntos
Animais , Masculino , Doença de Parkinson Secundária/induzido quimicamente , Cafeína/farmacologia , Oxidopamina/efeitos adversos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Estudos de Tempo e Movimento , Ratos Wistar , Hipocinesia/induzido quimicamente , Modelos Animais de Doenças , Transtornos Motores/induzido quimicamente , Atividade Motora/efeitos dos fármacosRESUMO
As it is a common observation that obesity tends to occur after discontinuation of exercise, we investigated how white adipocytes isolated from the periepididymal fat of animals with interrupted physical training transport and oxidize glucose, and whether these adaptations support the weight regain seen after 4 weeks of physical detraining. Male Wistar rats (45 days old, weighing 200 g) were divided into two groups (n=10): group D (detrained), trained for 8 weeks and detrained for 4 weeks; and group S (sedentary). The physical exercise was carried out on a treadmill for 60 min/day, 5 days/week for 8 weeks, at 50-60% of the maximum running capacity. After the training protocol, adipocytes isolated from the periepididymal adipose tissue were submitted to glucose uptake and oxidation tests. Adipocytes from detrained animals increased their glucose uptake capacity by 18.5% compared with those from sedentary animals (P<0.05). The same cells also showed a greater glucose oxidation capacity in response to insulin stimulation (34.55%) compared with those from the S group (P<0.05). We hypothesize that, owing to the more intense glucose entrance into adipose cells from detrained rats, more substrate became available for triacylglycerol synthesis. Furthermore, this increased glucose oxidation rate allowed an increase in energy supply for triacylglycerol synthesis. Thus, physical detraining might play a role as a possible obesogenic factor for increasing glucose uptake and oxidation by adipocytes.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças dos Trabalhadores Agrícolas/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Doença de Parkinson Secundária/induzido quimicamente , Praguicidas/toxicidade , California , Estudos de Casos e Controles , Modelos Estatísticos , Exposição Ocupacional/estatística & dados numéricos , Pontuação de Propensão , Fatores de RiscoRESUMO
Objective This study aimed to analyze the frequency of GSTP1-Alw26I polymorphism and to estimate its association with toxic substances in Parkinson's disease (PD). Methods A study group with 154 patients - subdivided into familial and sporadic PD groups - and 158 elderly individuals without the disease (control group) were evaluated. GSTP1-Alw26I polymorphism was analyzed by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Results Patients were significantly more exposed to pesticides compared with the control group (p=0.0004), and the heterozygote genotype associated to exposure to pesticides also prevailed in patients (p=0.0001). Wild homozygote genotype was related to tobacco use (p=0.043) and alcoholism (p=0.033) in familial PD patients. Conclusion Exposure to pesticides is associated to PD, whose effect can be enhanced when combined with the heterozygote genotype of GSTP1-Alw26I. Also, large genetic and environmental studies considering tobacco use, alcoholism, GSTP1 and PD are necessary to confirm our findings. .
Objetivo Analisar a frequência do polimorfismo GSTP1-Alw26I, assim como estimar sua associação com substâncias tóxicas na doença de Parkinson (DP). Métodos A casuística avaliada foi composta por um grupo de estudo, com 154 pacientes, subdivididos em DP familial e esporádica, e outro com 158 idosos sem a doença (grupo controle). O polimorfismo GSTP1-Alw26I foi analisado por reação em cadeia da polimerase/polimorfismo de comprimento do fragmento de restrição (PCR/RFLP). Resultados Os pacientes foram significativamente mais expostos a pesticidas, comparados com o grupo controle (p=0,0004), e o genótipo heterozigoto associado a exposição a pesticidas também prevaleceu nos pacientes (p=0,0001). O genótipo homozigoto selvagem apresentou relação com tabagismo (p=0,043) e etilismo (p=0,033) em pacientes com DP familial. Desse modo, a exposição a pesticidas está associada à DP, cujo efeito pode ser potencializado quando combinado ao genótipo heterozigoto de GSTP1-Alw26I. Estudos genético-ambientais envolvendo tabagismo, etilismo, GSTP1 e DP devem ser realizados em casuísticas numerosas, confirmando essa associação. .
Assuntos
Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , DNA-Citosina Metilases/genética , Glutationa S-Transferase pi/genética , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Praguicidas/toxicidade , Polimorfismo Genético/genética , DNA Metiltransferases Sítio Específica (Adenina-Específica)/genética , Estudos de Casos e Controles , Frequência do Gene , Heterozigoto , Reação em Cadeia da Polimerase , Fatores de Risco , Fatores SexuaisRESUMO
Objective To report the clinical and neuroimaging findings in a case series of vascular parkinsonism (VP). Methods Seventeen patients with VP were evaluated with motor, cognitive, and neuroimaging standardized tests and scales. Results All patients had arterial hypertension. Ten patients were male and the mean age of the whole sample was 75.8±10.1 years. The mean age of parkinsonism onset was 72.2±10.0 years. Common clinical features were urinary incontinence (88.2%), lower limb parkinsonism with freezing of gait and falls (82.3%), and pyramidal signs (76.4%). The mean Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn-Yahr scores were 72.5±21.6 points and 3.3±0.9 points, respectively. Sixteen (94.1%) patients had freezing of gait and executive dysfunction. Twelve (70.5%) patients had probable vascular dementia. The mean dose of levodopa was 530.9 mg/day. Unresponsiveness to the drug was confirmed by a 6.9 mean point reduction in the UPDRS score after the “practically defined off” test. Conclusion This series provides a profile of VP with predominant lower-limb involvement, freezing of gait and falls, pyramidal signs, executive dysfunction, concomitant vascular dementia, and poor levodopa response. .
Objetivo Relatar os achados clínicos e de neuroimagem em parkinsonismo vascular (PV). Métodos Foram avaliados 17 pacientes com PV do ponto de vista motor, cognitivo e de neuroimagem através de testes e escalas padronizados. Resultados Dos 17 pacientes, 10 (58,5%) eram homens; a média de idade média foi 75,8±10,1 anos. Todos os pacientes eram hipertensos; a média de idade do início do parkinsonismo foi 72,2±10,0 anos. Achados clínicos mais frequentes: incontinência urinária (88,2%); parkinsonismo de membros inferiores com bloqueio de marcha e quedas (82,3%); sinais piramidais (76,4%). A média dos escores UPDRS e Hoehn-Yahr foram, respectivamente, 72,5±21,6 e 3,3±0,9 pontos. Dezesseis pacientes (94,1%) apresentaram bloqueio de marcha e disfunção executiva. Doze pacientes (70,5%) preencheram critérios para demência vascular provável. A dose média de levodopa foi 530,9 mg/dia e os pacientes tiveram uma baixa resposta à droga, tendo havido redução de apenas 6,9 pontos em média no escore UPDRS após o teste “practically-defined off”. Conclusão O perfil de PV encontrado neste estudo foi caracterizado por: envolvimento predominante de membros inferiores, com bloqueio de marcha e quedas; sinais piramidais; disfunção executiva; demência vascular concomitante e resposta pobre à levodopa. .
Assuntos
Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Transtornos Cerebrovasculares/fisiopatologia , Doença de Parkinson Secundária/fisiopatologia , Atividades Cotidianas , Antiparkinsonianos/uso terapêutico , Estudos Transversais , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Hipertensão/complicações , Levodopa/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/etiologia , Fatores de Risco , Inquéritos e Questionários , Resultado do TratamentoRESUMO
A utilização de medicações psicoativas vem crescendo ao longo dos anos, sendo essencial o conhecimento de seus efeitos colaterais e interações medicamentosas. O desenvolvimento de distúrbios de movimento associados ao uso dessas substâncias é uma situação bastante desconfortável para o paciente, sendo essencial o diagnóstico adequado mediante forte suspeição. Relata-se o caso de um paciente que desenvolveu sintomas de parkinsonismo durante tratamento de hérnia discal lombar na vigência do uso de trazodona. É dada ênfase aos mecanismos de produção desse fenômeno e à sua condução clínica...
The use of psychoactive medications has been growing over years, being essential the knowledge of its side effects and interactions. The development of movement disturbances is a very uncomfortable situation for the patient, requiring a high suspicion for adequate diagnosis. A case of a patient who presented symptoms of Parkinsonism during use of Trazodone in the treatment of lumbar disc herniation is reported. Emphasis is given to the biological mechanisms of this phenomenon and its clinical conduction...
Assuntos
Humanos , Masculino , Adulto , Deslocamento do Disco Intervertebral/complicações , Doença de Parkinson Secundária/induzido quimicamente , Trazodona/efeitos adversosRESUMO
The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP+)-induced cellular model of Parkinson’s disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.
Assuntos
Animais , Ratos , /toxicidade , Autofagia/efeitos dos fármacos , Benzofuranos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/patologia , Apium/química , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Imuno-Histoquímica , Microscopia Eletrônica de Transmissão , Doença de Parkinson Secundária/induzido quimicamente , Sementes/químicaRESUMO
The goal of this review was to examine whether chronic Mn exposure produces dopamine neuron degeneration and PD or whether it has a distinct neuropathology and clinical presentation. I reviewed available clinical, neuroimaging, and neuropathological studies in humans and nonhuman primates exposed to Mn or other human conditions that result in elevated brain Mn concentrations. Human and nonhuman primate literature was examined to compare clinical, neuroimaging, and neuropathological changes associated with Mn-induced parkinsonism. Clinical, neuroimaging, and neuropathological evidence was used to examine whether Mn-induced parkinsonism involves degeneration of the nigrostriatal dopaminergic system as is the case in PD. The overwhelming evidence shows that Mn-induced parkinsonism does not involve degeneration of midbrain dopamine neurons and that l-dopa is not an effective therapy. New evidence is presented on a putative mechanism by which Mn may produce movement abnormalities. Confirmation of this hypothesis in humans is essential to make rational decisions about treatment, devise effective therapeutic strategies, and set regulatory guidelines.
O objetivo desta revisão foi examinar se a exposição crônica ao Mn produz degeneração do neurônio pela dopamina e DP ou se é apenas uma apresentação neuropatológica e clínica diferente. Foram revisados estudos clínicos, de neuroimagens e neuropatológicos disponíveis sobre humanos e primatas expostos ao Mn ou outras condições humanas que resultam em concentrações elevadas de Mn no cérebro. Foi examinada a literatura sobre humanos e primatas e comparadas as mudanças clínicas de neuroimagem e neuropatológicas associadas com o "parkinsonimo" induzido por Mn, envolvendo a degeneração do sistema dopaminérgico nigro-estriatal como no caso da DP. as evidências decisivas mostram que o "parkinsonismo" induzido pelo Mn não envolve a degeneração dos neurônios de dopamina do mesencéfalo e que o dopa-1 não é uma terapia eficaz. Novas evidências estão presentes em um mecanismo putativo pelo qual o Mn pode produzir anormalidades de movimento. A confirmação desta hipótese em humanos é essencial para tomar decisões adequadas sobre o tratamento, planejar estratégias terapêuticas eficazes e estabelecer guias regulatórios.
Assuntos
Animais , Humanos , Manganês/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , Neuroimagem , Doença de Parkinson Secundária/diagnóstico , Doenças dos Primatas/induzido quimicamente , Doenças dos Primatas/diagnósticoRESUMO
Clásicamente, la intoxicación aguda por órganofosforados produce una crisis colinérgica, que con frecuencia es continuada con un cuadro de debilidad muscular, expresión de un síndrome intermedio. La génesis de estos cuadros está relacionada con la inactivación de la acetilcolinesterasa por el insecticida. Mecanismos diferentes darían origen a polineuropatías y síndromes extrapiramidales tardíos. Se describe un paciente intoxicado agudamente con órganofosforados, que desarrolló una florida crisis colinérgica, que requirió ventilación mecánica invasiva. Después de tres semanas, ya recuperado de una neumonía y del síndrome colinérgico, se pudo definir un daño cognitivo de apariencia frontal, y se apreció la progresiva aparición de hipomimia, rigidez generalizada, bradikinesia y temblor, que configuraron un síndrome de Parkinson. Esta condición clínica se mantuvo al menos por dos semanas, siendo seguida de manera espontánea por una progresiva y completa mejoría del cuadro extrapiramidal y cognitivo. La literatura ha reportado, sólo por excepción casos similares, en los que se destacó tanto la aparición tardía del cuadro parkinsoniano, como su completa y espontánea remisión. Aunque la patogenia del cuadro parkinsoniano no está completamente establecida, existen evidencias experimentales que demuestran que los órganofosforados producen modificaciones en el transporte y en la recaptación de la dopamina. En este paciente se confirmó la doble acción patogénica de los órganofosforados, que habiéndose iniciado con un síndrome colinérgico agudo, finalizó con un compromiso dopaminérgico tardío. La completa recuperación de ambos efectos, permite encasillar a estos insecticidas como generadores de alteraciones funcionales, más que de gestores de daños o cambios estructurales.
Acute organophosphate poisoning usually produces a cholinergic crisis followed by muscular weakness or intermediate syndrome. The basis for these clinical manifestations is inactivation of acetylcholinesterase at the nicotinic and muscarinic nerve terminals and junctions. Different mechanism might lead to polyneuropathy and late extrapyramidal syndromes. We report a case of a male patient who ingested organophosphate with suicidal intentions. He developed a typical cholinergic crisis and required invasive mechanical ventilation. Three weeks later, frontal cognitive impairment was noticed and masklike face, generalized rigidity, bradykinesia and tremor progressively developed until a Parkinson syndrome was established. After his clinical condition had remained stable for at least two weeks, overt spontaneous improvement in motor and cognitive functions was observed. Similar reports in literature are infrequent. Although the pathophysiology that underlies extrapyramidal manifestations due organophosphate poisoning remains unclear, experimental evidence demostróte that organophosphate compounds impair dopamine transport and uptake. This case report suggests that organophosphate might act through a double pathogenic action i.e an initial acute cholinergic syndrome and a delayed disfunction in dopaminergic pathways. Complete spontaneous resolution of both effects allow us to classify organophosphate substances as a cause of functional impairment in the basal ganglia.
Assuntos
Humanos , Masculino , Adulto , Doença de Parkinson Secundária/induzido quimicamente , Inseticidas Organofosforados/efeitos adversos , Transtornos Cognitivos/induzido quimicamente , Inseticidas/intoxicação , Compostos Organofosforados , Remissão Espontânea , SíndromeRESUMO
The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.
Assuntos
Animais , Masculino , Ratos , Dopamina/fisiologia , Atividade Motora/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson Secundária/patologia , Substância Negra/citologia , Núcleo Subtalâmico/lesões , Imuno-Histoquímica , Atividade Motora/fisiologia , N-Metilaspartato , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Veículos Farmacêuticos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Distribuição Aleatória , Ratos Wistar , Substância Negra/fisiopatologia , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/patologia , Núcleo Subtalâmico/cirurgia , /metabolismoRESUMO
Bilateral and symmetric globus-pallidus hyperintensities are observed on T1-weighted MRI in most of the patients with chronic liver failure, due to manganese accumulation. We report a 53-year-old man, with rapid onset parkinsonism-dementia complex associated with accumulation of manganese in the brain, secondary to liver failure. A brain MRI was performed and a high signal on T1-weighted images was seen on globus-pallidus, as well as on T2-weighted images on the hemispheric white-matter. He was referred to a liver-transplantation. The patient passed away on the seventh postoperative day. Our findings support the concept of the toxic effects of manganese on the globus-pallidus. The treatment of this form of parkinsonism is controversial and liver-transplantation should not be considered as first line treatment but as an alternative one.
Hiperintesidades simétricas e bilaterais dos gânglios da base são observadas em imagens de ressonância magnética encefálica (RM) ponderadas em T1 na maioria dos pacientes com insuficiência hepática crônica devidas ao acúmulo de manganês. Nós relatamos o caso de um homem, com 53 anos de idade, com um complexo parkinsonismo-demência rapidamente progressivo associado com o acúmulo de manganês no cérebro, secundariamente a insuficiência hepática. Uma RM encefálica foi realizada e foram observadas imagens hiperintensas/hipersinal nas imagens ponderadas em T1 no globo pálido e, também, na substância branca dos hemisférios cerebrais ponderadas em T2. Devido à falta de resposta ao tratamento clinico optamos pelo transplante hepático. O paciente faleceu no 7° dia de PO. Nossos achados corroboram o conceito dos efeitos tóxicos do manganês nos gânglios da base/globo pálido. O tratamento desta forma de parkinsonismo é controverso e o transplante hepático não deverá ser considerada uma opção terapêutica de primeira linha, porém como um tratamento alternativo considerando-se os riscos-benefícios dessa escolha.