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1.
Elife ; 102021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34550070

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antiparkinsonianos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Animais Geneticamente Modificados , Antiparkinsonianos/uso terapêutico , Estudos de Casos e Controles , Bases de Dados Factuais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/genética , Doença de Gaucher/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
2.
Cells ; 10(8)2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34440619

RESUMO

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


Assuntos
Antioxidantes/metabolismo , Astrócitos/metabolismo , Autofagia , Proteínas de Drosophila/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Degeneração Neural , Transtornos Parkinsonianos/metabolismo , Proteínas Repressoras/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Animais Geneticamente Modificados , Antiparkinsonianos/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Autofagia/efeitos dos fármacos , Comportamento Animal , Di-Hidroxifenilalanina/análogos & derivados , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Masculino , Atividade Motora , Fator 2 Relacionado a NF-E2/genética , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Fenótipo , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Rotenona , Transdução de Sinais , Sirolimo/farmacologia
3.
Clin Neurophysiol ; 132(10): 2422-2430, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34454269

RESUMO

OBJECTIVE: Early postural instability (PI) is a red flag for the diagnosis of Parkinson's disease (PD). Several patients, however, fall within the first three years of disease, particularly when turning. We investigated whether PD patients, without clinically overt PI, manifest abnormal reactive postural responses to ecological perturbations resembling turning. METHODS: Fifteen healthy subjects and 20 patients without clinically overt PI, under and not under L-Dopa, underwent dynamic posturography during axial rotations around the longitudinal axis, provided by a robotic mechatronic platform. We measured reactive postural responses, including body displacement and reciprocal movements of the head, trunk, and pelvis, by using a network of three wearable inertial sensors. RESULTS: Patients showed higher body displacement of the head, trunk and pelvis, and lower joint movements at the lumbo-sacral junction than controls. Conversely, movements at the cranio-cervical junction were normal in PD. L-Dopa left reactive postural responses unchanged. CONCLUSIONS: Patients with PD without clinically overt PI manifest abnormal reactive postural responses to axial rotations, unresponsive to L-Dopa. The biomechanical model resulting from our experimental approach supports novel pathophysiological hypotheses of abnormal axial rotations in PD. SIGNIFICANCE: PD patients without clinically overt PI present subclinical balance impairment during axial rotations, unresponsive to L-Dopa.


Assuntos
Doença de Parkinson/fisiopatologia , Equilíbrio Postural/fisiologia , Robótica/métodos , Rotação , Dispositivos Eletrônicos Vestíveis , Idoso , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Diagnóstico Precoce , Feminino , Humanos , Levodopa/farmacologia , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Equilíbrio Postural/efeitos dos fármacos , Robótica/instrumentação
4.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281267

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Genótipo , Humanos , Levodopa/efeitos adversos , Levodopa/metabolismo , Levodopa/farmacologia , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/metabolismo , Farmacogenética/métodos , Farmacogenética/tendências , Variantes Farmacogenômicos , Pesquisa Médica Translacional
5.
Chem Biodivers ; 18(9): e2100204, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252268

RESUMO

Parkinson's disease (PD) is one of the most targeted neurodegenerative diseases in clinical research. Awareness of research is due to its increasing number of affected people worldwide. The pathology of PD has been linked to several key proteins upregulation such as the catechol O-Methyltransferase (COMT). Hence, the synthesis of compounds possessing inhibitory capacity has been the frontline of research in recent years. Several compounds have been synthesized among which is the nitrocatechol. However, major limitations associated with the nitrocatechol scaffold include the inability to possess adequate CNS penetration properties and hepatic toxicity associated with the compounds. However, a series of bicyclic hydroxypyridones compounds were synthesized to evaluate their inhibitory potentials on COMT protein with compound 38 (c38) 2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one shown to have a 40 fold increase level coverage in its IC50 over brain exposure when compared to the other synthesized compound. The molecular dynamics method was employed to understand the nature of interaction exhibited by c38. Molecular mechanics of c38 revealed a disruptive effect on the secondary structure of COMT protein. Per residue decomposition analysis revealed similar crucial residues involved in the favorable binding of c38 and tolcapone implicated its increased inhibitory capacity on COMT in preventing PD. Free binding energy (ΔGbind ) of c38 further revealed the inhibitory capacity towards COMT protein in comparison to the FDA approved tolcapone. Ligand mobility analysis of both compounds showed a timewise different mobility pattern across the simulation time frame at the active site pocket of the protein connoting the different inhibitory potency exhibited by c38 and tolcapone. Findings from this study revealed optimization of c38 could facilitate the discovery of new compounds with enhanced inhibitory properties towards COMT in treating PD.


Assuntos
Antiparkinsonianos/farmacologia , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Simulação de Dinâmica Molecular , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/química , Inibidores de Catecol O-Metiltransferase/química , Humanos , Estrutura Molecular , Doença de Parkinson/metabolismo , Termodinâmica
6.
PLoS One ; 16(7): e0255274, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34320022

RESUMO

OBJECTIVE: To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD). BACKGROUND: Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients. METHODS: The study participants consisted of 112 PD patients (median age 72.5 years [inter-quartile range: IQR 65-79]; mean disease duration 8.44 years [standard deviation: 7.33]; median Hoehn and Yahr stage 3 [IQR 2-3.75]) taking one of three types of non-ergot extended-release DAs (rotigotine 32; pramipexole 44; ropinirole 36) with or without L-dopa (median daily total dosage of antiparkinsonian drugs 525.5 mg [IQR 376.25-658] levodopa equivalent dose [LED]). Participants were assessed using the PD Sleep Scale-2 (PDSS-2). RESULTS: For the whole PD patient cohort, the PDSS-2 sleep disturbance domain score and the scores for item 1 assessing sleep quality and item 8 assessing nocturia were positively correlated with daily total dosage of antiparkinsonian drugs and dosage of L-dopa, but not with the dosage of DAs. Sub-analysis according to DA treatment revealed that DA dosage was not correlated with item 1 or 8 score in any of the subgroups. The LED ratio of rotigotine to the total dosage of antiparkinsonian drugs was inversely correlated with the item 1 score. CONCLUSIONS: These data suggest that antiparkinsonian drugs, in particular L-dopa, adversely affect nocturnal sleep in PD patients, especially in terms of sleep quality and nocturia. Thus, adjusting both the total dosage of antiparkinsonian drugs and the dose-ratio of L-dopa might be key actions for alleviating poor sleep quality in patients with PD. Among DAs, we found a clear positive correlation between the dose-ratio of rotigotine and sleep quality. Thus, partial L-dopa replacement with rotigotine could improve sleep quality in patients with PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Sono , Idoso , Antiparkinsonianos/farmacologia , Estudos Transversais , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Levodopa/farmacologia , Levodopa/uso terapêutico , Pramipexol/farmacologia , Pramipexol/uso terapêutico , Análise de Regressão , Estudos Retrospectivos , Sono/efeitos dos fármacos , Tetra-Hidronaftalenos/farmacologia , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico
7.
PLoS Comput Biol ; 17(7): e1009116, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233347

RESUMO

Parkinson's disease motor symptoms are associated with an increase in subthalamic nucleus beta band oscillatory power. However, these oscillations are phasic, and there is a growing body of evidence suggesting that beta burst duration may be of critical importance to motor symptoms. This makes insights into the dynamics of beta bursting generation valuable, in particular to refine closed-loop deep brain stimulation in Parkinson's disease. In this study, we ask the question "Can average burst duration reveal how dynamics change between the ON and OFF medication states?". Our analysis of local field potentials from the subthalamic nucleus demonstrates using linear surrogates that the system generating beta oscillations is more likely to act in a non-linear regime OFF medication and that the change in a non-linearity measure is correlated with motor impairment. In addition, we pinpoint the simplest dynamical changes that could be responsible for changes in the temporal patterning of beta oscillations between medication states by fitting to data biologically inspired models, and simpler beta envelope models. Finally, we show that the non-linearity can be directly extracted from average burst duration profiles under the assumption of constant noise in envelope models. This reveals that average burst duration profiles provide a window into burst dynamics, which may underlie the success of burst duration as a biomarker. In summary, we demonstrate a relationship between average burst duration profiles, dynamics of the system generating beta oscillations, and motor impairment, which puts us in a better position to understand the pathology and improve therapies such as deep brain stimulation.


Assuntos
Ritmo beta/fisiologia , Doença de Parkinson/fisiopatologia , Núcleo Subtalâmico/fisiologia , Núcleo Subtalâmico/fisiopatologia , Antiparkinsonianos/farmacologia , Ritmo beta/efeitos dos fármacos , Biologia Computacional , Humanos , Modelos Neurológicos , Núcleo Subtalâmico/efeitos dos fármacos
8.
Sci Rep ; 11(1): 13154, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162989

RESUMO

This study aimed to identify potential novel drug candidates and targets for Parkinson's disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.


Assuntos
Antiparkinsonianos/isolamento & purificação , Descoberta de Drogas , Terapia de Alvo Molecular , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacologia , Linhagem Celular , Mineração de Dados/métodos , Bases de Dados Genéticas , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Transporte de Elétrons/genética , Metabolismo Energético/genética , Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Transporte de Íons/genética , Redes e Vias Metabólicas/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doença de Parkinson/genética , Mapeamento de Interação de Proteínas
9.
Toxicol Lett ; 349: 1-11, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34052309

RESUMO

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


Assuntos
Antiparkinsonianos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Glibureto/farmacologia , Inflamassomos/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Degeneração Neural , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Inflamassomos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Maneb , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia
10.
Biomed Pharmacother ; 139: 111525, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33882412

RESUMO

3-Hydroxytyrosol (HXT) is a natural polyphenol present in extra virgin olive oil. It is a key component of Mediterranean diet and is known for its strong antioxidant activity. The present study evaluated the potential of HXT as an anti-parkinsonian molecule in terms of its ability to inhibit MAO-B and thereby maintaining dopamine (DA) levels in Parkinson's disease (PD). In-silico molecular docking study followed by MMGBSA binding free energy calculation revealed that HXT has a strong binding affinity for MAO-B in comparison to MAO-A. Moreover, rasagiline and HXT interacted with the similar binding sites and modes of interactions. Additionally, molecular dynamics simulation studies revealed stable nature of HXT-MAO-B interaction and also provided information about the amino acid residues involved in binding. Moreover, in vitro studies revealed that HXT inhibited MAO-B in human platelets with IC50 value of 7.78 µM. In vivo studies using MPTP-induced mouse model of PD revealed increase in DA levels with concomitant decrease in DA metabolites (DOPAC and HVA) on HXT treatment. Furthermore, MAO-B activity was also inhibited on HXT administration to PD mice. In addition, HXT treatment prevented MPTP-induced loss of DA neurons in substantia nigra and their nerve terminals in the striatum. HXT also attenuated motor impairments in PD mice assessed by catalepsy bar, narrow beam walk and open field tests. Thus, the present findings reveal HXT as a potential inhibitor of MAO-B, which may be used as a lead molecule for the development of therapeutics for PD.


Assuntos
Antiparkinsonianos/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Simulação por Computador , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Humanos , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monoaminoxidase/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/patologia , Azeite de Oliva/química , Doença de Parkinson Secundária/patologia , Álcool Feniletílico/farmacologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia
11.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799684

RESUMO

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15-45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans.


Assuntos
Envelhecimento/fisiologia , Modelos Animais de Doenças , Perda Auditiva Neurossensorial/tratamento farmacológico , Selegilina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacologia , Limiar Auditivo/efeitos dos fármacos , Limiar Auditivo/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Selegilina/administração & dosagem , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
12.
Eur J Pharmacol ; 903: 174112, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33901458

RESUMO

In the present study, we investigated the anti-Parkinson's effect of vanillic acid (VA) (12 mg/kg, 25 mg/kg, 50 mg/kg p.o.) against rotenone (2 mg/kg s.c.) induced Parkinson's disease (PD) in rats. The continuous administration of rotenone for 35 days resulted in rigidity in muscles, catalepsy, and decrease in locomotor activity, body weight, and rearing behaviour along with the generation of oxidative stress in the brain (rise in the TBARS, and SAG level and reduced CAT, and GSH levels). Co-treatment of VA and levodopa-carbidopa (100 mg/kg + 25 mg/kg p.o.) lead to a significant (P < 0.001) reduction in the muscle rigidity and catalepsy along with a significant (P < 0.001) increase in body weight, rearing behaviour, locomotion and muscle activity as compared to the rotenone-treated group in the dose dependent manner, showing maximum effect at the 50 mg/kg. It also showed reversal of levels of oxidative stress parameters thus, reducing the neuronal oxidative stress. The level of DA was also estimated which showed an increase in the level of DA in the VA plus standard drug treated animals as compared to rotenone treated group. Histopathological evaluation showed a high number of eosinophilic lesions in the rotenone group which were found to be very less in the VA co-treated group. The study thus proved that co-treatment of VA and levodopa-carbidopa, significantly protected the brain from neuronal damage due to oxidative stress and attenuated the motor defects indicating the possible therapeutic potential of VA as a neuroprotective in PD.


Assuntos
Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Ácido Vanílico/farmacologia , Ácido Vanílico/uso terapêutico , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carbidopa/farmacologia , Carbidopa/uso terapêutico , Catalase/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Dopamina/metabolismo , Combinação de Medicamentos , Feminino , Glutationa/metabolismo , Levodopa/farmacologia , Levodopa/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Equilíbrio Postural/efeitos dos fármacos , Ratos Sprague-Dawley , Rotenona/toxicidade , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
13.
Angew Chem Int Ed Engl ; 60(33): 18022-18030, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-33904641

RESUMO

Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A2A adenosine receptor and activate the D2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.


Assuntos
Antiparkinsonianos/farmacologia , Desenho de Fármacos , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D2/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
14.
J Neurol ; 268(7): 2506-2514, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33544218

RESUMO

BACKGROUND: Sleep disturbances are common in Parkinson's Disease (PD), with nocturnal akinesia being one of the most burdensome. Levodopa is frequently used in clinical routine to improve nocturnal akinesia, although evidence is not well proven. METHODS: We assessed associations of Levodopa intake with quality of sleep and perception of nocturnal akinesia in three PD cohorts, using the Parkinson's Disease Sleep Scale (PDSS-2) in two cohorts and a question on nocturnal immobility in one cohort. In one cohort also objective assessment of mobility during sleep was performed, using mobile health technology. RESULTS: In an independent analysis of all three cohorts (in total n = 1124 PD patients), patients taking Levodopa CR reported a significantly higher burden by nocturnal akinesia than patients without Levodopa. Higher Levodopa intake and MDS-UPDRS part IV scores (indicating motor fluctuations) predicted worse PDSS-2 and higher subjective nocturnal immobility scores, while disease duration and severity were not predictive. Levodopa intake was not associated with objectively changed mobility during sleep. CONCLUSION: Our results showed an association of higher Levodopa intake with perception of worse quality of sleep and nocturnal immobility in PD, indicating that Levodopa alone might not be suitable to improve subjective feeling of nocturnal akinesia in PD. In contrast, Levodopa intake was not relevantly associated with objectively measured mobility during sleep. PD patients with motor fluctuations may be particularly affected by subjective perception of nocturnal mobility. This study should motivate further pathophysiological and clinical investigations on the cause of perception of immobility during sleep in PD.


Assuntos
Doença de Parkinson , Transtornos do Sono-Vigília , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Humanos , Levodopa/uso terapêutico , Movimento , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Sono , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/etiologia
15.
Commun Biol ; 4(1): 232, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608634

RESUMO

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson's disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-ßsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-ßsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-ßsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-ßsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.


Assuntos
Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Intoxicação por MPTP/tratamento farmacológico , Neurônios/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Peptídeos/farmacologia , alfa-Sinucleína/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Células HEK293 , Humanos , Intoxicação por MPTP/genética , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Mutação , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ratos Sprague-Dawley , alfa-Sinucleína/genética
16.
Commun Biol ; 4(1): 203, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589689

RESUMO

We recently linked branched-chain amino acid transferase 1 (BCAT1) dysfunction with the movement disorder Parkinson's disease (PD), and found that RNAi-mediated knockdown of neuronal bcat-1 in C. elegans causes abnormal spasm-like 'curling' behavior with age. Here we report the development of a machine learning-based workflow and its application to the discovery of potentially new therapeutics for PD. In addition to simplifying quantification and maintaining a low data overhead, our simple segment-train-quantify platform enables fully automated scoring of image stills upon training of a convolutional neural network. We have trained a highly reliable neural network for the detection and classification of worm postures in order to carry out high-throughput curling analysis without the need for user intervention or post-inspection. In a proof-of-concept screen of 50 FDA-approved drugs, enasidenib, ethosuximide, metformin, and nitisinone were identified as candidates for potential late-in-life intervention in PD. These findings point to the utility of our high-throughput platform for automated scoring of worm postures and in particular, the discovery of potential candidate treatments for PD.


Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Reposicionamento de Medicamentos , Ensaios de Triagem em Larga Escala , Postura , Animais , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Interpretação de Imagem Assistida por Computador , Aprendizado de Máquina , Redes Neurais de Computação , Estudo de Prova de Conceito , Interferência de RNA , Transaminases/genética , Transaminases/metabolismo , Fluxo de Trabalho
17.
Biochem Pharmacol ; 189: 114402, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33387482

RESUMO

UDP-glucuronosyltransferases (UGTs) are enzymes catalyzing the glucuronidation of various endogenous and exogenous compounds. In this study, we examined the possibility that N6-methyladenosine (m6A) modification affects hepatic UGT expression. Treatment of HepaRG cells with 3-deazaadenosine, an inhibitor of RNA methylation, significantly increased UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B15 mRNA levels (1.3- to 2.6-fold). Among them, we focused on UGT2B7 because it most highly contributes to glucuronidation of clinically used drugs. Methylated RNA immunoprecipitation assays revealed that UGT2B7 mRNA in HepaRG cells and human livers is subjected to m6A modification mainly at the 5' untranslated region (UTR) and secondarily at the 3'UTR. UGT2B7 mRNA and protein levels in Huh-7 cells were significantly increased by double knockdown of methyltransferase-like 3 (METTL3) and METTL14, whereas those were decreased by knockdown of fat mass and obesity-associated protein (FTO) or alkB homolog 5, RNA demethylase (ALKBH5), suggesting that m6A modification downregulates UGT2B7 expression. By experiments using actinomycin D, an inhibitor of transcription, it was demonstrated that ALKBH5-mediated demethylation would attenuate UGT2B7 mRNA degradation, whereas METTL3/METTL14 or FTO-mediated m6A modification would alter the transactivity of UGT2B7. Luciferase assays revealed that the promoter region at -118 to -106 has a key role in the decrease in transactivity of UGT2B7 by FTO knockdown. We found that hepatocyte nuclear factor 4α (HNF4α) expression was significantly decreased by knockdown of FTO, indicating that this would be the underlying mechanism of the decreased transactivity of UGT2B7 by knockdown of FTO. Interestingly, treatment with entacapone, which is used for the treatment of Parkinson's disease and is an inhibitor of FTO, decreased HNF4α and UGT2B7 expression. In conclusion, this study clarified that RNA methylation posttranscriptionally controls hepatic UGT2B7 expression.


Assuntos
Adenosina/análogos & derivados , Glucuronosiltransferase/biossíntese , Glucuronosiltransferase/genética , Fígado/fisiologia , Processamento Pós-Transcricional do RNA/fisiologia , Adenosina/genética , Adenosina/metabolismo , Adulto , Antiparkinsonianos/farmacologia , Catecóis/farmacologia , Linhagem Celular , Feminino , Expressão Gênica , Glucuronosiltransferase/antagonistas & inibidores , Humanos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Nitrilas/farmacologia , Processamento Pós-Transcricional do RNA/efeitos dos fármacos
18.
J Mol Neurosci ; 71(4): 702-712, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33403591

RESUMO

Previous evidence has shown a link between neurodegenerative diseases, including Parkinson's disease (PD), and melatonin. The data in the literature about the impact of the hormone under different experimental PD conditions are quite controversial, and its effect on memory impairment in the disease is very poorly explored. The current research was aimed at investigating the role of melatonin pretreatment on memory and motor behavior in healthy rats and those with the partial 6-hydroxydopamine (6-OHDA) model of PD. All rodents were pretreated with melatonin (20 mg/kg, intraperitoneally) for 5 days. At 24 h and 7 days after the first treatment for healthy rats, and at the second and third week post-lesion for those with PD, the animals were tested behaviorally (apomorphine-induced rotations, rotarod, and passive avoidance tests). The neurochemical levels of dopamine (DA), acetylcholine (ACh), noradrenaline (NA), and serotonin (Sero) in the brain were also determined. The results showed that in healthy animals, melatonin pretreatment had amnestic and motor-suppressive effects and did not change the levels of measured brain neurotransmitters. In animals with PD, melatonin pretreatment exerted a neuroprotective effect, manifested as a significantly decreased number of apomorphine-induced rotations, reduced number of falls in the rotarod test, and improved memory performance. The brain DA and ACh concentrations in the same animals were restored to the control levels, and those of NA and Sero did not change. Our results demonstrate a beneficial effect of melatonin on memory and motor disturbance in 6-OHDA-lesioned rats.


Assuntos
Antiparkinsonianos/uso terapêutico , Melatonina/uso terapêutico , Memória , Movimento , Doença de Parkinson/tratamento farmacológico , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Melatonina/administração & dosagem , Melatonina/farmacologia , Neurotransmissores/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Ratos , Ratos Wistar
19.
J Neural Transm (Vienna) ; 128(1): 73-81, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33392826

RESUMO

Advanced Parkinson's disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu2) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu2 PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10 mg/kg), after which their behaviour was rated. CBiPES 10 mg/kg reduced global dyskinesia by 60% (P < 0.0001), while peak dose dyskinesia was reduced by 66% (P < 0.001), compared to L-DOPA/vehicle. CBiPES 10 mg/kg also diminished global PLBs by 56% (P < 0.0001), while peak dose PLBs were reduced by 64% (P < 0.001), compared to L-DOPA/vehicle. Lastly, CBiPES enhanced the anti-parkinsonian action of L-DOPA, by reducing global parkinsonian disability by 43% (P < 0.01), compared to L-DOPA/vehicle. Our results provide further evidence that mGlu2 positive allosteric modulation may be an approach that could be efficacious for the treatment of dyskinesia, psychosis and motor fluctuations in PD.


Assuntos
Discinesia Induzida por Medicamentos , Transtornos Parkinsonianos , Transtornos Psicóticos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Comportamento Animal , Callithrix , Discinesia Induzida por Medicamentos/tratamento farmacológico , Humanos , Levodopa , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico
20.
Neurotoxicology ; 83: 129-136, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33450328

RESUMO

Clinical and experimental findings support the view that activation of hippocampus microglia through NADPH oxidase contributes to cognitive impairment in Parkinson's disease (PD). Taurine, an antioxidant, displays an exclusive physical property on brain function, such as learning and memory. To date, the role of taurine in improving cognitive impairment in PD is not fully uncovered. Hence, we evaluated the protective effect of taurine on cognitive ability and explored the related mechanism in the model built by paraquat and maneb (P + M)-induced PD mice. Then the ability of learning and memory was observed by Morris water maze, neuron loss was evaluated by immunohistochemistry in hippocampus, the level of postsynaptic density 95 (PSD95) and microglia activation was assessed by immunostaining, the molecules (gp91phox, p47phox, mac1, p-Src/Src and p-Erk/Erk) were examined by western blot. The results showed that taurine could alleviate the impairments in learning and memory induced by P + M injection in mice (decreased escape latency on day 4, P < 0.01; decreased swimming distance on day 4, P < 0.05; increased percent time in target quadrant, P < 0.05), corresponding with activation of microglia (decreased IBa-1 density, P < 0.001; decreased the protein expression of p47phox, P < 0.05; decreased protein expression of gp91phox, P < 0.01; decreased p-Src/Src, P < 0.01; decreased p-Erk/Erk, P < 0.01; decreased mac 1, P < 0.01), decreased neuron loss (increased number of NeurN+ neuron, P < 0.001; increased protein expression of NeruN, P < 0.01; decreased protein expression of caspase 3, P < 0.01) and increased PSD95 level in hippocampus (P < 0.01). The results indicated that mac1 and Src-Erk signaling was involved in increased NADPH oxidase expression in hippocampus microglia of P + M mice, and taurine could improve injuries in learning and memory through mac1 reduction. The new findings in mac1 triggering hippocampal microglia NADPH oxidase through Src/Erk pathway of the present study might provide a therapy target for PD.


Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Hipocampo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Taurina/farmacologia , Animais , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Antígeno de Macrófago 1/metabolismo , Masculino , Maneb , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Degeneração Neural , Neurônios/metabolismo , Neurônios/patologia , Paraquat , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Fosforilação , Transdução de Sinais , Quinases da Família src/metabolismo
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