RESUMEN
L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D2 receptor (D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D2R+ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D2R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D2-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D2R+ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D2R+ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D2R+ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D2R+ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Asunto(s)
Discinesia Inducida por Medicamentos , Trastornos Parkinsonianos , Ratas , Animales , Levodopa/toxicidad , Dopamina , Trastornos Parkinsonianos/tratamiento farmacológico , Oxidopamina , Cuerpo Estriado/metabolismo , Neuronas/metabolismo , Receptores de Dopamina D2/metabolismo , Antiparkinsonianos/toxicidadRESUMEN
The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-O-methyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 µM) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.
Asunto(s)
Antiparkinsonianos , Inhibidores de Catecol O-Metiltransferasa , Teratógenos , Animales , Antiparkinsonianos/toxicidad , Catecol O-Metiltransferasa/metabolismo , Dopamina/metabolismo , Oxadiazoles , Pez Cebra/metabolismo , Inhibidores de Catecol O-Metiltransferasa/toxicidad , Teratógenos/toxicidadRESUMEN
Parkinson's disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson's disease.
Asunto(s)
Antiparkinsonianos/farmacología , Ensayos Analíticos de Alto Rendimiento , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Agregación Patológica de Proteínas , Taninos/farmacología , alfa-Sinucleína/metabolismo , Animales , Animales Modificados Genéticamente , Antiparkinsonianos/toxicidad , Benzotiazoles/química , Bioensayo , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Células HeLa , Humanos , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Agregado de Proteínas , Espectrometría de Fluorescencia , Taninos/toxicidad , alfa-Sinucleína/genética , alfa-Sinucleína/ultraestructuraRESUMEN
Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.
Asunto(s)
Antiparkinsonianos/toxicidad , Dopaminérgicos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Callithrix , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Discinesia Inducida por Medicamentos/prevención & control , Células HEK293 , Humanos , Ligandos , Trastornos Parkinsonianos/prevención & control , Primates , Estructura Secundaria de Proteína , Quinpirol/farmacología , Quinpirol/uso terapéutico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/químicaRESUMEN
PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.
Asunto(s)
Antiparkinsonianos/farmacología , Levodopa/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Psicóticos/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/toxicidad , Conducta Animal/efectos de los fármacos , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/farmacología , Callithrix , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/prevención & control , Femenino , Indoles/administración & dosificación , Indoles/farmacología , Levodopa/administración & dosificación , Levodopa/toxicidad , Masculino , Trastornos Parkinsonianos/psicología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Trastornos Psicóticos/etiología , Piridinas/administración & dosificación , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: The gold-standard treatment for Parkinson's disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine leading to its uncontrolled release as a "false neurotransmitter". The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood. OBJECTIVE: This study aimed to investigate the functionality of 5-HT1A receptors using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed "off" L-DOPA. METHODS: Each rat underwent a positron emission tomography scan with [18F]F13640, a 5-HT1AR agonist which labels receptors in a high affinity state for agonists, or with [18F]MPPF, a 5-HT1AR antagonist which labels all the receptors. RESULTS: There were decreases of [18F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18F]F13640 uptake was decreased bilaterally in the globus pallidus and thalamus. On the non-lesioned side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side. CONCLUSION: These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson's disease and levodopa-induced dyskinesia. In particular, these observations suggest a substantial involvement of the functional state of 5-HT1AR in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions.
Asunto(s)
Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Antiparkinsonianos/toxicidad , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/metabolismoRESUMEN
Parkinson's disease (PD) psychosis afflicts over half of patients and poses a significant burden on quality of life. The aetiology of PD psychosis is multifactorial and likely arises from the complex interaction between dopamine replacement therapy and disease state. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset is a validated model to predict the efficacy of therapeutic compounds for treatment-related complications, including PD psychosis. In this model, psychosis-like behaviours (PLBs) encompass stereotypies that are idiosyncratic in nature and reproducible with each L-3,4-dihydroxyphenylanaline (L-DOPA) administration. In the present study, we sought to expand upon the existing repertoire of PLBs through the characterisation of novel stereotypical behaviours that appear dependent on the environment. We then discuss our findings in the context of clinical reports on stereotypical behaviours termed "punding" in subjects with PD, which consists of stereotypical repetitive and senseless behaviours. The poor understanding of the pathophysiology governing punding and consequent lack of effective therapies stand to benefit from enhanced characterisation of these stereotypical behaviours in a validated pre-clinical model. We hope that further characterisation of PLBs in the MPTP-lesioned marmoset will be helpful in the evaluation of interventions that seek to alleviate PD psychosis symptoms.
Asunto(s)
Antiparkinsonianos/toxicidad , Levodopa/toxicidad , Trastornos Parkinsonianos/psicología , Trastornos Psicóticos/fisiopatología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Conducta Animal/efectos de los fármacos , Callithrix , Modelos Animales de Enfermedad , Femenino , Masculino , Trastornos Parkinsonianos/fisiopatología , Trastornos Psicóticos/etiologíaRESUMEN
L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.
Asunto(s)
Discinesia Inducida por Medicamentos/prevención & control , Discinesia Inducida por Medicamentos/fisiopatología , Ritmo Gamma/efectos de los fármacos , Ketamina/uso terapéutico , Levodopa/toxicidad , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Antiparkinsonianos/toxicidad , Relación Dosis-Respuesta a Droga , Ritmo Gamma/fisiología , Ketamina/farmacología , Masculino , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
Interferon-γ (IFN-γ) is a proinflammatory cytokine that activates glial cells. IFN-γ is increased in the plasma and brain of Parkinson's disease patients, suggesting its potential role in the disease. We investigated whether the IFN-γ deficiency could interfere with nigrostriatal degeneration induced by the neurotoxin 6-hydroxydopamine, L-DOPA-induced dyskinesia, and the neuroinflammatory features as astrogliosis, microgliosis, and induced nitric oxide synthase (iNOS) immunoreactivity induced by L-DOPA treatment. Wild type (WT) and IFN-γ knockout (IFN-γ/KO) mice received unilateral striatal microinjections of 6-hydroxydopamine. Animals were sacrificed 1, 3, 7, and 21 days after lesions. Additional group of WT and IFN-γ/KO parkinsonian mice, after 3 weeks of neurotoxin injection, received L-DOPA (intraperitoneally, for 21 days) resulting in dyskinetic-like behavior. Tyrosine hydroxylase immunostaining indicated the starting of dopaminergic lesion since the first day past toxin administration, progressively increased until the third day when it stabilized. There was no difference in the lesion and L-DOPA-induced dyskinesia intensity between WT and IFN-γ/KO mice. Remarkably, IFN-γ/KO mice treated with L-DOPA presented in the lesioned striatum an increase of iNOS and glial fibrilary acid protein (GFAP) density, compared with the WT group. Morphological analysis revealed the rise of astrocytes and microglia reactivity in IFN-γ/KO mice exibiting dyskinesia. In conclusion, IFN-γ/KO mice presented an intensification of the inflammatory reaction accompanying L-DOPA treatment and suggest that iNOS and GFAP increase, and the activation of astrocytes and microglia induced afterward L-DOPA treatment was IFN-γ independent events. Intriguingly, IFN-γ absence did not affect the degeneration of dopaminergic neurons or LID development.
Asunto(s)
Antiparkinsonianos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Mediadores de Inflamación/metabolismo , Interferón gamma/deficiencia , Levodopa/toxicidad , Trastornos Parkinsonianos/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Discinesia Inducida por Medicamentos/genética , Discinesia Inducida por Medicamentos/patología , Interferón gamma/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidopamina/toxicidad , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patologíaRESUMEN
Physical exercise attenuates the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in 6-hydroxydopamine-induced hemiparkinsonian mice through unknown mechanisms. We now tested if exercise normalizes the aberrant corticostriatal neuroplasticity associated with experimental murine models of LID. C57BL/6 mice received two unilateral intrastriatal injections of 6-hydroxydopamine (12 µg) and were treated after 3 wk with l-DOPA/benserazide (25/12.5 mg/kg) for 4 wk, with individualized moderate-intensity running (60%-70% VÌo2peak) or not (untrained). l-DOPA converted the pattern of plasticity in corticostriatal synapses from a long-term depression (LTD) into a long-term potentiation (LTP). Exercise reduced LID severity and decreased aberrant LTP. These results suggest that exercise attenuates abnormal corticostriatal plasticity to decrease LID.
Asunto(s)
Antiparkinsonianos/toxicidad , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Discinesia Inducida por Medicamentos/prevención & control , Terapia por Ejercicio , Levodopa/toxicidad , Plasticidad Neuronal/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Benserazida/toxicidad , Corteza Cerebral/fisiopatología , Cuerpo Estriado/fisiopatología , Dihidroxifenilalanina/análogos & derivados , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/fisiopatología , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Carrera , Factores de TiempoRESUMEN
BACKGROUND: Autophagy is intensively studied in cancer, metabolic and neurodegenerative diseases, but little is known about its role in pathological conditions linked to altered neurotransmission. We examined the involvement of autophagy in levodopa (l-dopa)-induced dyskinesia, a frequent motor complication developed in response to standard dopamine replacement therapy in parkinsonian patients. METHODS: We used mouse and non-human primate models of Parkinson's disease to examine changes in autophagy associated with chronic l-dopa administration and to establish a causative link between impaired autophagy and dyskinesia. RESULTS: We found that l-dopa-induced dyskinesia is associated with accumulation of the autophagy-specific substrate p62, a marker of autophagy deficiency. Increased p62 was observed in a subset of projection neurons located in the striatum and depended on l-dopa-mediated activation of dopamine D1 receptors, and mammalian target of rapamycin. Inhibition of mammalian target of rapamycin complex 1 with rapamycin counteracted the impairment of autophagy produced by l-dopa, and reduced dyskinesia. The anti-dyskinetic effect of rapamycin was lost when autophagy was constitutively suppressed in D1 receptor-expressing striatal neurons, through inactivation of the autophagy-related gene protein 7. CONCLUSIONS: These findings indicate that augmented responsiveness at D1 receptors leads to dysregulated autophagy, and results in the emergence of l-dopa-induced dyskinesia. They further suggest the enhancement of autophagy as a therapeutic strategy against dyskinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Discinesia Inducida por Medicamentos , Trastornos Parkinsonianos , Animales , Antiparkinsonianos/toxicidad , Autofagia , Cuerpo Estriado , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , Humanos , Levodopa/toxicidad , Ratones , OxidopaminaRESUMEN
Administration of L-3,4-dihydroxyphenylalanine (L-DOPA) provides Parkinson's disease patients with effective symptomatic relief. However, long-term L-DOPA therapy is often marred by complications such as dyskinesia. We have previously demonstrated that serotonin type 3 (5-HT3) receptor blockade with the clinically available and highly selective antagonist ondansetron alleviates dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to explore the antidyskinetic efficacy of granisetron, another clinically available 5-HT3 receptor antagonist. Rats were rendered hemi-parkinsonian by 6-OHDA injection in the medial forebrain bundle. Following induction of stable abnormal involuntary movements (AIMs), granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle was acutely administered in combination with L-DOPA and the severity of AIMs, both duration and amplitude, was determined. We also assessed the effect of granisetron on L-DOPA antiparkinsonian action by performing the cylinder test. Adding granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) to L-DOPA resulted in a significant reduction of AIMs duration and amplitude, with certain parameters being reduced by as much as 38 and 45% (P < 0.05 and P < 0.001, respectively). The antidyskinetic effect of granisetron was not accompanied by a reduction of L-DOPA antiparkinsonian action. These results suggest that 5-HT3 blockade may reduce L-DOPA-induced dyskinesia without impairing the therapeutic efficacy of L-DOPA. However, a U-shaped dose-response curve obtained with certain parameters may limit the therapeutic potential of this strategy and require further investigation.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Granisetrón/farmacología , Levodopa/toxicidad , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Animales , Antiparkinsonianos/farmacología , Antiparkinsonianos/toxicidad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Femenino , Granisetrón/administración & dosificación , Levodopa/farmacología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT3/administración & dosificaciónRESUMEN
AIM: To screen the zinc database for structurally similar molecules to compound 23 that targets DJ1 for use as a neuroprotective agent for Parkinson's disease. BACKGROUND: Parkinson's disease (PD) is the second most common chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra. To date, several proteins account for the recessive familial PD-forms, namely, Parkin, PINK-1, DJ-1, SNCA, PARK2, and LRRK2 Genes. DJ1 is one of the important central points that may be targeted for PD therapy. Recently, Compound 23 has been observed to exert the neuroprotective effect against neurodegeneration in a PD model, but due to its toxic substructure, the hunt for better nontoxic compounds continues. OBJECTIVE: The overall objective of our work is to apply in silico approaches to screen structure similar compounds that interact potentially with DJ1 and may serve as a good therapeutic molecule for PD. METHODS: Initial data mining was done from the zinc database and then screened compounds were additionally screened with toxicity checker, carcinopred, ADMET analysis and docking analysis. RESULTS: The basic screening of database for structurally similar chemicals to compound 23 resulted in 50 compounds, which were further screened to twenty-three and finally seven compounds have been screened based on the toxicity and carcinopred test. Later, the seven compounds were docked and analysed for docking efficiency with DJ1. Our result of molecular docking and molecular simulation analysis highlights Molecule 42(SS2) to exhibit best binding affinity against DJ-1 protein target and can be proposed to be used as a therapeutic agent to modulate neurodegenerative proteins. CONCLUSION: Therefore, we conclude the discovery of novel, non-toxic, non-carcinogenic, ADMET investigated, capable of crossing BB barrier but structurally similar compounds to Compound-23, specifically molecule 42(SS2) and potentially molecule 34(SS1) to be used as neuroprotective agents for Parkinson's disease.
Asunto(s)
Antiparkinsonianos/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Proteína Desglicasa DJ-1/metabolismo , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/toxicidad , Simulación por Computador , Neuronas Dopaminérgicas/patología , Descubrimiento de Drogas/métodos , Humanos , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/toxicidad , Enfermedad de Parkinson/fisiopatologíaRESUMEN
BACKGROUND: Levodopa (l-dopa) is the frontline treatment for motor symptoms of Parkinson's disease. However, prolonged use of l-dopa results in a motor complication known as levodopa-induced dyskinesia (LID) in ~50% of patients over 5 years. OBJECTIVES: We investigated neurovascular abnormalities in a rat model of LID by examining changes in angiogenesis and dopamine-dependent vessel diameter changes. METHODS: Differences in striatal and nigral angiogenesis in a parkinsonian rat model (6-OHDA lesion) treated with 2 doses of l-dopa (saline, 2, and 10 mg/kg/day subcutaneous l-dopa treatment for 22 days) by 5-bromo-2'-deoxyuridine (BrdU)-RECA1 co-immunofluorescence. Difference in the vasomotor response to dopamine was examined with 2-photon laser scanning microscopy and Dodt gradient imaging. RESULTS: We found that the 10 mg/kg l-dopa dosing regimen induced LID in all animals (n = 5) and induced significant angiogenesis in the striatum and substantia nigra. In contrast, the 2 mg/kg treatment induced LID in 6 out of 12 rats and led to linearly increasing LID severity over the 22-day treatment period, making this a promising model for studying LID progression longitudinally. However, no significantly different level of angiogenesis was observed between LID versus non-LID animals. Dopamine-induced vasodilatory responses were exaggerated only in rats that show LID-like signs compared to the rest of groups. Additionally, in juvenile rats, we showed that DA-induced vasodilation is preceded by increased Ca2+ release in the adjacent astrocytes. CONCLUSION: This finding supports that astrocytic dopamine signaling controls striatal blood flow bidirectionally, and the balance is altered in LID. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Animales , Antiparkinsonianos/toxicidad , Cuerpo Estriado , Modelos Animales de Enfermedad , Dopamina , Humanos , Levodopa/toxicidad , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , RatasRESUMEN
Dyskinesia induced by long-term L-Dopa (LID) therapy in Parkinson disease is associated with altered striatal function whose molecular bases remain unclear. Here, a transcriptomic approach was applied for comprehensive analysis of distinctively regulated genes in striatal tissue, their specific pathways, and functional- and disease-associated networks in a rodent model of LID. This approach has identified transforming growth factor beta type 1 (TGFß1) as a highly upregulated gene in dyskinetic animals. TGFß1 pathway is a top aberrantly regulated pathway in the striatum following LID development based on differentially expressed genes (> 1.5 fold change and P < 0.05). The induction of TGFß1 pathway specific genes, TGFß1, INHBA, AMHR2 and PMEPA1 was also associated with regulation of NPTX2, PDP1, SCG2, SYNPR, TAC1, TH, TNNT1 genes. Transcriptional network and upstream regulator analyses have identified AKT-centered functional and ERK-centered disease networks revealing the association of TGFß1, IL-1ß and TNFα with LID development. Therefore, results support that TGFß1 pathway is a major contributor to the pathogenic mechanisms of LID.
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Discinesia Inducida por Medicamentos/metabolismo , Transducción de Señal , Transcriptoma , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Antiparkinsonianos/toxicidad , Encéfalo/metabolismo , Discinesia Inducida por Medicamentos/genética , Redes Reguladoras de Genes , Subunidades beta de Inhibinas/genética , Subunidades beta de Inhibinas/metabolismo , Levodopa/toxicidad , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Neurotransmisores/genética , Receptores de Neurotransmisores/metabolismo , Taquicininas/genética , Taquicininas/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Regulación hacia ArribaRESUMEN
Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1 mg/kg, P < 0.05; - 38% with 1 mg/kg, P < 0.01; - 47% with 10 mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.
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Antiparkinsonianos/farmacología , Ganglios Basales/efectos de los fármacos , Levodopa/farmacología , Moclobemida/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Antiparkinsonianos/toxicidad , Ganglios Basales/enzimología , Ganglios Basales/fisiopatología , Conducta Animal/efectos de los fármacos , Callithrix , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/fisiopatología , Femenino , Levodopa/toxicidad , Masculino , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/fisiopatología , Psicosis Inducidas por Sustancias/etiología , Psicosis Inducidas por Sustancias/psicologíaRESUMEN
CONTEXT: L-DOPA is the first-line drug for Parkinson's disease (PD). However, chronic use can lead to dyskinesia. Caffeine, which is a known neuroprotectant, can potentially act as an adjunct to minimise adverse effects of L-DOPA. OBJECTIVES: This study determined changes in terms of neurodegeneration, locomotion and mechanosensation in Caenorhabditis elegans (Rhabditidae) strain UA57 overexpressing tyrosine hydroxylase (CAT-2) when treated with caffeine, L-DOPA or their combinations. MATERIALS AND METHODS: Neurodegeneration was monitored via fluorescence microscopy of GFP-tagged dopaminergic neurons in the head and tail regions of C. elegans (n = 20). Meanwhile, mechanosensation and locomotion under vehicle (0.1% DMSO), L-DOPA (60 mM), caffeine (10 mM) or 60 mM L-DOPA + 10 or 20 mM caffeine (60LC10 and 60LC20) treatments were scored for 3 days. RESULTS: L-DOPA (60 mM) reduced CEP and ADE neurons by 4.3% on day 3, with a concomitant decrease in fluorescence by 44.6%. This correlated with reductions in gentle head (-35%) and nose touch (-40%) responses, but improved locomotion (20-75%) compared with vehicle alone. CEP and ADE neuron counts were preserved with caffeine (10 mM) or 60LC10 (98-100%), which correlated with improved mechanosensation (10-23%) and locomotion (18-76%). However, none of the treatments was able to preserve PDE neuron count, reducing the basal slowing response. Discussion and conclusions: Taken together, we show that caffeine can protect DAergic neurons and can reduce aberrant locomotion and loss of sensation when co-administered with L-DOPA, which can potentially impact PD treatment and warrants further investigation.
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Cafeína/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Locomoción/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Animales Modificados Genéticamente , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/toxicidad , Caenorhabditis elegans , Cafeína/administración & dosificación , Relación Dosis-Respuesta a Droga , Levodopa/administración & dosificación , Levodopa/toxicidad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/fisiopatologíaRESUMEN
Levo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease; however, most patients develop uncontrollable abnormal involuntary movements known as L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesia can be reduced by pallidotomy of the medial globus pallidus or pallidal deep brain stimulation, suggesting that the medial globus pallidus plays a significant role in the development of L-DOPA-induced dyskinesia. In the present study, the pathological changes of the medial globus pallidus in L-DOPA-induced dyskinesia were studied in rat models of Parkinson's disease (unilateral 6-hydroxydopamine lesioning) and L-DOPA-induced dyskinesia (L-DOPA injection in Parkinson's disease-model rats twice daily for 2 weeks, confirmed by display of dyskinesia-like abnormal involuntary movements). L-DOPA-induced dyskinesia-model rats displayed medial globus pallidus hypertrophy, enlarged axon terminals surrounding the dendrites of medial globus pallidus neurons, and increased density of synaptic vesicles in enlarged axon terminals on the lesioned side. Synaptic terminal enlargement reversed after discontinuation of L-DOPA. Histological studies revealed the enlarged synaptic terminals were those of GABAergic striatal (direct pathway) neurons. A single injection of L-DOPA enhanced GABA release in the medial globus pallidus on the lesioned side in L-DOPA-induced dyskinesia-model rats compared to Parkinson's disease-model rats. In addition, microinjection of muscimol, a GABAA receptor agonist, into the medial globus pallidus on the lesioned side of Parkinson's disease-model rats induced dyskinesia-like abnormal involuntary movements. Microinjection of bicuculline, a GABAA receptor antagonist, into the medial globus pallidus on the lesioned side alleviated L-DOPA-induced dyskinesia in Parkinson's disease-model rats that had received L-DOPA prior to the microinjection. These results indicate that priming for L-DOPA-induced dyskinesia comprises excessive GABA storage in axon terminals of the direct pathway and that expression of L-DOPA-induced dyskinesia is associated with enhanced GABA release into the medial globus pallidus after L-DOPA dosing and the resultant excessive stimulation of GABAA receptors.
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Antiparkinsonianos/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Globo Pálido/metabolismo , Levodopa/toxicidad , Trastornos Parkinsonianos/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Globo Pálido/efectos de los fármacos , Masculino , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacosRESUMEN
Numerous genes, and alterations in their expression, have been identified as risk factors for developing levodopa-induced dyskinesia (LID). However, our understanding of the complexities of molecular changes remains insufficient for development of clinical treatment. In the current study we used gene array, in situ hybridization, immunohistochemistry, and microdialysis to provide a unique compare and contrast assessment of the relationship of four candidate genes to LID, employing three genetically distinct rat strains (Sprague-Dawley (SD), Fischer-344 (F344) and Lewis-RT.1) showing differences in dyskinesia susceptibility and 'first-ever LID' versus 'chronic LID' expression in subjects displaying equal dyskinesia severity. In these studies, rat strains were easily distinguishable for their LID propensity with: 1) a majority of SD rats expressing LID (LID+) and a subset being resistant (LID-); 2) all F344 rats readily developing (LID+); and 3) all Lewis rats being LID-resistant (LID-). Following chronic levodopa, LID+ SD rats showed significant increases in candidate gene expression: Nr4a2/(Nurr1) > > Trh > Inhba = Fosb. However, SD rats with long-standing striatal dopamine (DA) depletion treated with first-ever versus chronic high-dose levodopa revealed that despite identical levels of LID severity: 1) Fosb and Nurr1 transcripts but not protein were elevated with acute LID expression; 2) FOSB/ΔFOSB and NURR1 proteins were elevated only with chronic LID; and 3) Trh transcript and protein were elevated only with chronic LID. Strikingly, despite similar levodopa-induced striatal DA release in both LID-expressing F344 and LID-resistant Lewis rats, Fosb, Trh, Inhba transcripts were significantly elevated in both strains; however, Nurr1 mRNA was significantly increased only in LID+ F344 rats. These findings suggest a need to reevaluate currently accepted genotype-to-phenotype relationships in the expression of LID, specifically that of Fosb, a transcription factor generally assumed to play a causal role, and Nurr1, a transcription factor that has received significant attention in PD research linked to its critical role in the survival and function of midbrain DA neurons but who's striatal expression, generally below levels of detection, has remained largely unexplored as a regulator of LID. Finally these studies introduce a novel 'model' (inbred F344 vs inbred Lewis) that may provide a powerful tool for investigating the role for 'dyskinesia-resistance' genes downstream of 'dyskinesia-susceptibility' genes in modulating LID expression, a concept that has received considerably less attention and offers a new ways of thinking about antidyskinetic therapies.
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Antiparkinsonianos/toxicidad , Discinesia Inducida por Medicamentos/genética , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Genotipo , Masculino , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Fenotipo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas LewRESUMEN
L-dopa induced dyskinesia (LID) is a debilitating side-effect of the primary treatment used in Parkinson's disease (PD), l-dopa. Here we investigate the effect of HU-308, a cannabinoid CB2 receptor agonist, on LIDs. Utilizing a mouse model of PD and LIDs, induced by 6-OHDA and subsequent l-dopa treatment, we show that HU-308 reduced LIDs as effectively as amantadine, the current frontline treatment. Furthermore, treatment with HU-308 plus amantadine resulted in a greater anti-dyskinetic effect than maximally achieved with HU-308 alone, potentially suggesting a synergistic effect of these two treatments. Lastly, we demonstrated that treatment with HU-308 and amantadine either alone, or in combination, decreased striatal neuroinflammation, a mechanism which has been suggested to contribute to LIDs. Taken together, our results suggest pharmacological treatments with CB2 agonists merit further investigation as therapies for LIDs in PD patients. Furthermore, since CB2 receptors are thought to be primarily expressed on, and signal through, glia, our data provide weight to suggestion that neuroinflammation, or more specifically, altered glial function, plays a role in development of LIDs.