RESUMEN
Parkinsonism in rats induced by the pesticide rotenone is one of the most adequate models of Parkinson's disease (PD). Isatin (indole-2,3-dione) is an endogenous regulator found in mammals and humans and exhibiting a wide range of biological activities mediated by numerous isatin-binding proteins, including those associated with neurodegenerative pathology. A course of rotenone administration to rats caused behavioral impairments and changes in the profile and relative content of isatin-binding proteins in the brain. In this study, we have investigated the delayed neuroprotective effect of isatin (5 days after completion of the course of rotenone administration) on behavioral reactions and the relative content of isatin-binding proteins in the brain of rats with rotenone-induced experimental parkinsonism. Although during this period the rats retained locomotor dysfunction, the proteomic analysis data (profile of isatin-binding proteins in the brain and changes in their relative content) differed from the results obtained immediately after completion of the course of rotenone administration. Moreover, all isatin-binding proteins with altered relative content changed during this period are associated to varying degrees with neurodegeneration (many with Parkinson's and Alzheimer's diseases).
Asunto(s)
Encéfalo , Isatina , Fármacos Neuroprotectores , Rotenona , Animales , Isatina/farmacología , Rotenona/toxicidad , Fármacos Neuroprotectores/farmacología , Ratas , Masculino , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Ratas Wistar , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/patología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Modelos Animales de Enfermedad , Levodopa , Fármacos Neuroprotectores , Oxidopamina , Óxido de Zinc , Animales , Levodopa/farmacología , Ratas , Fármacos Neuroprotectores/farmacología , Óxido de Zinc/química , Óxido de Zinc/farmacología , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Nanopartículas del Metal/química , Nanopartículas/química , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/patología , Enfermedad de Parkinson Secundaria/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas WistarRESUMEN
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.
Asunto(s)
Antiparkinsonianos , Monoaminooxidasa , Estrés Oxidativo , Rotenona , Pez Cebra , Animales , Masculino , Antiparkinsonianos/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , Rotenona/toxicidadRESUMEN
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.
Asunto(s)
Bacillus subtilis , Escherichia coli , Microbioma Gastrointestinal , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Probióticos , Rotenona , alfa-Sinucleína , Animales , Ratones , Microbioma Gastrointestinal/fisiología , Probióticos/uso terapéutico , Probióticos/farmacología , alfa-Sinucleína/metabolismo , Estrés Oxidativo/efectos de los fármacos , Rotenona/toxicidad , Lacticaseibacillus casei/fisiología , Metionina-ARNt Ligasa , Triptófano-ARNt Ligasa/fisiología , Masculino , Tetrahidrofolato Deshidrogenasa/metabolismo , Simulación por Computador , Trastornos Parkinsonianos/microbiología , Humanos , Fármacos Neuroprotectores/uso terapéutico , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Enfermedad de Parkinson Secundaria/inducido químicamente , Neuronas Dopaminérgicas/efectos de los fármacos , Enfermedad de Parkinson/microbiologíaRESUMEN
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.
Asunto(s)
MicroARNs , Microglía , Fármacos Neuroprotectores , Ratas Wistar , Rotenona , Animales , MicroARNs/genética , MicroARNs/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Masculino , Ratas , Modelos Animales de Enfermedad , Dopamina/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Tirosina 3-Monooxigenasa/metabolismo , Tirosina 3-Monooxigenasa/genéticaRESUMEN
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.
Asunto(s)
Mitocondrias , Estrés Oxidativo , Ratas Sprague-Dawley , Canales Catiónicos TRPC , alfa-Sinucleína , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Animales , Ratas , Estrés Oxidativo/efectos de los fármacos , Humanos , Canales Catiónicos TRPC/genética , Canales Catiónicos TRPC/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Línea Celular Tumoral , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/inducido químicamente , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Sistema de Señalización de MAP Quinasas , Ratones Endogámicos C57BL , Estrés Oxidativo , Animales , Masculino , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Ácidos Grasos Monoinsaturados/farmacología , Ácidos Grasos Monoinsaturados/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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.
Asunto(s)
MicroARNs , Paraquat , alfa-Sinucleína , Animales , MicroARNs/metabolismo , alfa-Sinucleína/metabolismo , Paraquat/toxicidad , Masculino , Ratas , Ratas Wistar , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Modelos Animales de Enfermedad , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Vietnam-era veterans were exposed to Agent Orange (AO), which is associated with a high prevalence of Parkinson's disease (PD). However, little is known about the development of PD-like symptoms caused by drug-induced parkinsonism (DIP) in such populations. This study aimed to investigate PD incidence and PD risk following exposure to AO or DIP-risk drugs in veterans. METHODS: A retrospective cohort study was conducted using 12 years (2009-2020) of electronic medical records of the Veterans Health Service Medical Center, the largest Veterans Affairs hospital in South Korea (n = 37,246; 100% male; age, 65.57 ± 8.12 years). Exposure to AO or DIP-risk drugs, including antipsychotic, prokinetic, anti-epileptic, dopamine-depleting and anti-anginal agents, was assessed in veterans with PD, operationally defined as having a PD diagnosis and one or more prescriptions for PD treatment. The PD risk was calculated using multiple logistic regression analysis adjusted for age and comorbidities. RESULTS: The rates of DIP-risk drug use and AO exposure were 37.92% and 62.62%, respectively. The PD incidence from 2010 to 2020 was 3.08%; 1.30% with neither exposure, 1.63% with AO exposure, 4.38% with DIP-risk drug use, and 6.33% with both. Combined exposure to AO and DIP-risk drugs increased the PD risk (adjusted odds ratio = 1.68, 95% confidence interval, 1.36-2.08, P < 0.001). CONCLUSIONS: The PD incidence was 1.31 times higher with AO exposure alone and 1.68 times higher with AO exposure and DIP-risk drug use. The results suggest the necessity for careful monitoring and DIP-risk drug prescription in patients with AO exposure.
Asunto(s)
Enfermedad de Parkinson Secundaria , Enfermedad de Parkinson , Veteranos , Humanos , Masculino , Anciano , Femenino , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Estudios Retrospectivos , Agente Naranja/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/diagnósticoRESUMEN
BACKGROUND: The disease burden of parkinsonism is extremely costly in the United States. Unlike Parkinson's disease, drug-induced parkinsonism (DIP) is acute and reversible; exploring the causative drug is important to prevent DIP in patients at high-risk of parkinsonism. OBJECTIVE: To examine whether the use of gastrointestinal (GI) prokinetics is associated with an increased risk of parkinsonism. METHODS: We conducted a case-crossover study using nationally representative data. We included patients who were newly diagnosed with parkinsonism (ICD-10 G20, G21.1, G25.1) between January 1, 2007 and December 1, 2015. The first prescription date of G20, G21.1, or G25.1 diagnoses was defined as the index date (0 day). Patients with prior extrapyramidal and movement disorders or brain tumors were excluded. We assessed the exposure within the risk (0-29 days) and control periods (60-89 days), before or on the index date. Conditional logistic regression estimated the adjusted odds ratio (aOR) for parkinsonism. RESULTS: Overall, 2268 and 1674 patients were exposed to GI prokinetics during the risk and control periods, respectively. The use of GI prokinetics significantly increased the occurrence of parkinsonism (aOR = 2.31; 95% Confidence Interval [CI], 2.06-2.59). The use of GI prokinetics was associated with a higher occurrence of parkinsonism in elderly patients (≥65 years old; aOR = 2.69; 95% CI, 2.30-3.14) than in younger patients (aOR = 1.90; 95% CI, 1.59-2.27). CONCLUSIONS: The use of GI prokinetics was significantly associated with higher occurrences of parkinsonism, necessitating close consideration when using GI prokinetics.
Asunto(s)
Enfermedad de Parkinson Secundaria , Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Estados Unidos/epidemiología , Anciano , Estudios Cruzados , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/epidemiología , Estudios de Casos y Controles , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/epidemiologíaRESUMEN
Military recruits exposed to TCE decades ago have increased risk of the brain disease.
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Exposición a Riesgos Ambientales , Enfermedad de Parkinson Secundaria , Contaminantes del Suelo , Tricloroetileno , Contaminantes del Agua , Humanos , Enfermedad de Parkinson Secundaria/inducido químicamente , Contaminantes del Suelo/toxicidad , Solventes/toxicidad , Tricloroetileno/toxicidad , Contaminantes del Agua/toxicidadRESUMEN
Background: Neuroinflammation is involved in the development of Parkinson's disease (PD). Calhm2 plays an important role in the development of microglial inflammation, but whether Calhm2 is involved in PD and its regulatory mechanisms are unclear. Methods: To study the role of Calhm2 in the development of PD, we utilized conventional Calhm2 knockout mice, microglial Calhm2 knockout mice and neuronal Calhm2 knockout mice, and established the MPTP-induced PD mice model. Moreover, a series of methods including behavioral test, immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, western blot, mass spectrometry analysis and co-immunoprecipitation were utilized to study the regulatory mechanisms. Results: We found that both conventional Calhm2 knockout and microglial Calhm2 knockout significantly reduced dopaminergic neuronal loss, and decreased microglial numbers, thereby improving locomotor performance in PD model mice. Mechanistically, we found that Calhm2 interacted with EFhd2 and regulated downstream STAT3 signaling in microglia. Knockdown of Calhm2 or EFhd2 both inhibited downstream STAT3 signaling and inflammatory cytokine levels in microglia. Conclusion: We demonstrate the important role of Calhm2 in microglial activation and the pathology of PD, thus providing a potential therapeutic target for microglia-mediated neuroinflammation-related diseases.
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Canales de Calcio , Enfermedad de Parkinson Secundaria , Animales , Ratones , Proteínas de Unión al Calcio , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/patología , Enfermedades Neuroinflamatorias , Transducción de Señal , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/genética , Canales de Calcio/genéticaRESUMEN
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.
Asunto(s)
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Enfermedad de Parkinson Secundaria , Enfermedad de Parkinson , Humanos , Antivirales/uso terapéutico , Estudios de Cohortes , Enfermedad de Parkinson/epidemiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Hepacivirus , Respuesta Virológica Sostenida , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/complicaciones , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Carcinoma Hepatocelular/tratamiento farmacológicoRESUMEN
We report the singular case of a 31-year-old woman who developed very serious Fluphenazine-induced parkinsonism over a few days due to a doubly incongruent drug prescription by indication and dosage having been applied to a healthy subject over one week instead of seven months. Unlike gradual drug-induced parkinsonism, our patient experienced acute extrapyramidal syndrome (EPS), reaching significant motor and sphincter disability in just a few days, followed by a gradual incomplete recovery over more than six months. In fact, after drug discontinuation, hypomimia and slight left hemi-somatic rigidity with bradykinesia remained, as well as stable non-progressive memory disturbances. Despite bio-humoral and instrumental investigations and DaTScan were negative, MRI post-analysis evidenced a 6.5% loss in brain volume. Specifically, irreversible cortical and sub-cortical grey matter reduction and cerebrospinal fluid space enlargement with spared white matter were found. Our observations suggest that the sudden availability of Fluphenazine results in a kind of plateau effect of parkinsonism presentation, partially reversible due to the neurotoxic drug effect on the cortical and sub-cortical grey matter, resulting in asymmetric EPS and stable memory loss, respectively. Our report confirms the debated neurotoxicity of first-generation neuroleptics and the postulated theory of differential susceptibility to the cytotoxic stressors on the central nervous system.
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Antipsicóticos , Enfermedad de Parkinson Secundaria , Trastornos Parkinsonianos , Femenino , Humanos , Adulto , Flufenazina/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Antipsicóticos/efectos adversos , Amnesia , Trastornos de la Memoria/inducido químicamenteRESUMEN
Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.
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Antipsicóticos , Cinarizina , Enfermedad de Parkinson Secundaria , Trastornos Parkinsonianos , Humanos , Anciano , Flunarizina/efectos adversos , Cinarizina/efectos adversos , Bloqueadores de los Canales de Calcio/efectos adversos , Estudios Prospectivos , Trastornos Parkinsonianos/inducido químicamente , Enfermedad de Parkinson Secundaria/inducido químicamente , Antagonistas de Dopamina/efectos adversos , Antipsicóticos/efectos adversos , SíndromeRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and its incidence is predicted to increase worldwide. Striatal dopamine depletion caused by substantia nigra (SN) degeneration is a pathological hallmark of PD and is strongly associated with cardinal motor and non-motor symptoms. Previous studies have reported that exercise increases neuroplasticity and promotes neurorestoration by increasing neurotrophic factors and synaptic strength and stimulating neurogenesis in PD. In the present study, we found that rotarod walking exercise, a modality of motor skill learning training, improved locomotor disturbances and reduced nigrostriatal degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, our exercise regimen improved MPTP-induced perturbation of adult neurogenesis in some areas of the brain, including the subventricular zone, subgranular zone, SN, and striatum. Moreover, rotarod walking activated the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and induced brain-derived neurotrophic factor (BDNF) expression in these regions. The results suggest that motor skill learning training using rotarod walking improves adult neurogenesis and restores motor performance by modulating the AMPK/BDNF pathway. Therefore, our findings provide evidence for neuroprotective effects and improved neuroplasticity in PD through motor skill learning training.
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Enfermedad de Parkinson Secundaria , Caminata , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Ventrículos Laterales/metabolismo , Ratones , Ratones Endogámicos C57BL , Neurogénesis , Enfermedad de Parkinson Secundaria/inducido químicamente , Sustancia Negra/metabolismoRESUMEN
In a rotenone-induced Parkinson's disease (PD) rat model, behavioral investigation, pathological examination, inflammatory factor analysis, and mitochondrial structure and function investigation verified the anti-PD efficacy of nardosinone. A combined transcriptome and proteome analysis proposed that the anti-PD target of nardosinone is the slc38a2 gene and may involve the GABAergic synaptic pathway and cAMP-signaling pathway. Analysis of targeted slc38a2 knockout cells and expression of key enzyme-encoding genes in both pathways verified the target and pathways proposed by the 'omics analysis. This further confirms that nardosinone can regulate the slc38a2 gene, a potential new target for the treatment of Parkinson's disease, and plays an anti-PD role through the GABAergic synaptic and cAMP pathways.
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Enfermedad de Parkinson Secundaria , Enfermedad de Parkinson , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson Secundaria/inducido químicamente , Sesquiterpenos Policíclicos , Ratas , Rotenona/farmacologíaRESUMEN
Animal models for Parkinson's disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. The present study compared two commonly used neurotoxininduced mouse models of chronic PD to guide model selection, explore the pathogenesis and mechanisms underlying PD and develop effective treatments. The chronic PD mouse models were established via treatment with rotenone or 1methyl4phenyl1,2,3,6-tetrahydropyridine (MPTP) for 6 weeks. The effects of rotenone and MPTP in the mice were compared by assessing neurobehavior, neuropathology and mitochondrial function through the use of the pole, rotarod and open field tests, immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), ionized calciumbinding adapter molecule 1 (Iba1), neuronal nuclear antigen (NeuN) and (p)S129 αsynuclein, immunofluorescence for GFAP, Iba1 and NeuN, western blotting for TH, oxygen consumption, complex I enzyme activity. The locomotor activity, motor coordination and exploratory behavior in both rotenone and MPTP groups were significantly lower compared with the control group. However, behavioral tests were no significant differences between the two groups. In the MPTP group, the loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta, the reduction of the tyrosine hydroxylase content in the SN and striatum and the astrocyte proliferation and microglial activation in the SN were more significant compared with the rotenone group. Notably, mitochondrialdependent oxygen consumption and complex I enzyme activity in the SN were significantly reduced in the rotenone group compared with the MPTP group. In addition, Lewy bodies were present only in SN neurons in the rotenone group. Although no significant differences in neurobehavior were observed between the two mouse models, the MPTP model reproduced the pathological features of PD more precisely in terms of the loss of DA neurons, decreased dopamine levels and neuroinflammation in the SN. On the other hand, the rotenone model was more suitable for studying the role of mitochondrial dysfunction (deficient complex I activity) and Lewy body formation in the SN, which is a characteristic pathological feature of PD. The results indicated that MPTP and rotenone PD models have advantages and disadvantages, therefore one or both should be selected based on the purpose of the study.
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Modelos Animales de Enfermedad , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/fisiopatología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Reacción de Prevención/fisiología , Western Blotting , Enfermedad Crónica , Proteínas de Unión al ADN/metabolismo , Neuronas Dopaminérgicas/citología , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunohistoquímica , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Proteínas del Tejido Nervioso/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Rotenona , Sustancia Negra/citología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Although mounting studies have been conducted, no effective therapy is available to halt its progression. Indole-3-carbinol (I3C) is a naturally occurring compound obtained by ß-thioglucosidase-mediated autolysis of glucobrassicin in cruciferous vegetables. Besides its powerful antioxidant activity, I3C has shown neuroprotection against depression and chemically induced neurotoxicity via its anti-inflammatory and antiapoptotic effects. This study aimed to investigate the neuroprotective effects of I3C against rotenone (ROT)-induced PD in male albino rats. The possible protective mechanisms were also explored. PD was induced by subcutaneous administration of ROT (2 mg/kg) for 28 days. The effects of I3C (25, 50, and 100 mg/kg/day) were assessed by catalepsy test (bar test), spontaneous locomotor activity, rotarod test, weight change, tyrosine hydroxylase (TH) expression, α-synuclein (α-Syn) expression, striatal dopamine (DA) content, and histological examination. The highest dose of I3C (100 mg/kg) was the most effective to prevent ROT-mediated motor dysfunctions and amend striatal DA decrease, weight loss, neurodegeneration, TH expression reduction, and α-Syn expression increase in both the midbrain and striatum. Further mechanistic investigations revealed that the neuroprotective effects of I3C are partially attributed to its anti-inflammatory and antiapoptotic effects and the activation of the sirtuin 1/AMP-activated protein kinase pathway. Altogether, these results suggested that I3C could attenuate biochemical, molecular, and functional changes in a rat PD model with following repeated rotenone exposures.
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Indoles/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/prevención & control , Rotenona , Sirtuina 1/metabolismo , Desacopladores , Animales , Peso Corporal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Dopamina/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Enfermedad de Parkinson Secundaria/psicología , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sirtuina 1/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , alfa-Sinucleína/biosíntesis , alfa-Sinucleína/efectos de los fármacosRESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disorder associated with dopamine neuron loss and motor dysfunction. Neuroprotective agents that prevent dopamine neuron death hold great promise for slowing the disease's progression. The activation of cannabinoid (CB) receptors has shown neuroprotective effects in preclinical models of neurodegenerative disease, traumatic brain injury, and stroke, and may provide neuroprotection against PD. Here, we report that the selective CB2 agonist GW842166x exerted protective effects against the 6-hydroxydopamine (6-OHDA)-induced loss of dopamine neurons and its associated motor function deficits in mice, as shown by an improvement in balance beam walking, pole, grip strength, rotarod, and amphetamine-induced rotation tests. The neuroprotective effects of GW842166x were prevented by the CB2 receptor antagonist AM630, suggesting a CB2-dependent mechanism. To investigate potential mechanisms for the neuroprotective effects of GW842166x, we performed electrophysiological recordings from substantia nigra pars compacta (SNc) dopamine neurons in ex vivo midbrain slices prepared from drug-naïve mice. We found that the bath application of GW842166x led to a decrease in action potential firing, likely due to a decrease in hyperpolarization-activated currents (Ih) and a shift of the half-activation potential (V1/2) of Ih to a more hyperpolarized level. Taken together, the CB2 agonist GW842166x may reduce the vulnerability of dopamine neurons to 6-OHDA by decreasing the action potential firing of these neurons and the associated calcium load.