RESUMEN
Blonanserin is a second-generation antipsychotic for the treatment of schizophrenia. Blonanserin has two different routes of administration: oral tablets/powder and transdermal patches. The aim of this study was to investigate as a post-hoc analysis of an original study whether switching from blonanserin tablets/powders to transdermal patches would reduce extrapyramidal symptoms (EPS) and/or the dose of antiparkinsonian drugs for the stabilization of blood pharmacokinetics in patients with schizophrenia. Patients with schizophrenia (n = 155) were enrolled in either cohort 1 or 2. In cohort 1 (n = 97), patients received 40-80 mg/day blonanserin transdermal patches for one year after taking 8-16 mg/day blonanserin tablets for 6 weeks, and the dose of patches was determined based on the dose of the tablets. In cohort 2 (n = 58), all patients started with 40 mg/day blonanserin patches and then received 40-80 mg/day for a year after taking blonanserin tablets/powders. Changes from the start of transdermal patch treatment in EPS and the dose of antiparkinsonian drugs at 3, 6, and 12 months were assessed using the Drug-Induced EPS Scale (DIEPSS) and biperiden equivalents of total antiparkinsonian drugs (BPD-eq), respectively. Among 155 patients, only four patients in cohort 1 discontinued owing to EPS during a patch period. Significant improvements from the start of patch treatment in the DIEPSS total score at any point were observed (mean change±SD): -0.44 ± 1.50 (p = 0.013), -0.07 ± 1.78 (p = 0.73), and - 0.14 ± 1.37 (p = 0.44) in cohort 1 and - 0.16 ± 1.32 (p = 0.40), -0.74 ± 1.92 (p = 0.020), and - 0.81 ± 2.22 (p = 0.047) in cohort 2 at 3, 6, and 12 months, respectively. In contrast, there were no significant changes from the start of patch treatment in BPD-eq at any month (p > 0.05). Transdermal patches of blonanserin are a more effective route of administration to diminish EPS than oral tablets/powder.
Asunto(s)
Discinesias/prevención & control , Piperazinas , Piperidinas , Polvos , Esquizofrenia/tratamiento farmacológico , Comprimidos , Parche Transdérmico , Administración Oral , Adulto , Antiparkinsonianos , Antipsicóticos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéuticoRESUMEN
L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson's Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminished sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons facilitates the formation and expression of LID. We find that the pharmacological activation of Smoothened, a downstream effector of Shh, attenuates LID in the neurotoxic 6-OHDA- and genetic aphakia mouse models of Parkinson's Disease. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from dopamine neurons or Smoothened activity in cholinergic interneurons promotes LID. Conversely, the selective expression of constitutively active Smoothened in cholinergic interneurons is sufficient to render the sensitized aphakia model of Parkinson's Disease resistant to LID. Furthermore, acute depletion of Shh from dopamine neurons through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa.
Asunto(s)
Dopamina/metabolismo , Discinesias/prevención & control , Proteínas Hedgehog/metabolismo , Levodopa/efectos adversos , Enfermedad de Parkinson/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , RatonesRESUMEN
Parkinson disease (PD) and other related diseases with α-synuclein pathology are associated with a long prodromal or preclinical stage of disease. Predictive models based on diagnosis of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) make it possible to identify people in the prodromal stage of synucleinopathy who have a high probability of future disease and provide an opportunity to implement neuroprotective therapies. However, rehabilitation providers may be unaware of iRBD and the motor abnormalities that indicate early motor system dysfunction related to α-synuclein pathology. Furthermore, there is no existing rehabilitation framework to guide early interventions for people with iRBD. The purpose of this work is to (1) review extrapyramidal signs of motor system dysfunction in people with iRBD and (2) propose a framework for early protective or preventive therapies in prodromal synucleinopathy using iRBD as a predictive marker. Longitudinal and cross-sectional studies indicate that the earliest emerging motor deficits in iRBD are bradykinesia, deficits performing activities of daily living, and abnormalities in speech, gait, and posture. These deficits may emerge up to 12 years before a diagnosis of synucleinopathy. The proposed rehabilitation framework for iRBD includes early exercise-based interventions of aerobic exercise, progressive resistance training, and multimodal exercise with rehabilitation consultations to address exercise prescription, progression, and monitoring. This rehabilitation framework may be used to implement neuroprotective, multidisciplinary, and proactive clinical care in people with a high likelihood of conversion to PD, dementia with Lewy bodies, or multiple systems atrophy.
Asunto(s)
Discinesias , Terapia por Ejercicio , Rehabilitación Neurológica , Síntomas Prodrómicos , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Discinesias/etiología , Discinesias/fisiopatología , Discinesias/prevención & control , Discinesias/rehabilitación , Humanos , Trastorno de la Conducta del Sueño REM/complicaciones , Trastorno de la Conducta del Sueño REM/fisiopatología , Trastorno de la Conducta del Sueño REM/prevención & control , Trastorno de la Conducta del Sueño REM/rehabilitación , Sinucleinopatías/complicaciones , Sinucleinopatías/fisiopatología , Sinucleinopatías/prevención & control , Sinucleinopatías/rehabilitaciónRESUMEN
BACKGROUND: Neonatal therapeutic hypothermia (TH) can ameliorate or prevent the development of dyskinetic cerebral palsy (CP) after hypoxic-ischemic encephalopathy (HIE). The Dyskinesia Impairment Scale (DIS) was recently launched to quantify dyskinetic (dystonic and choreatic) motor features in patients with CP. In TH treated children, who are at risk of developing dyskinetic CP, we aimed to determine DIS-scores at pre-school age. METHOD: In 21 Dutch pre-school children (3-6 years of age) who had received TH according to the Dutch-Flemish treatment protocol, we determined DIS-scores. We associated DIS-scores with 1. age-matched control values (Kuiper et al., 2018) [1], and 2. previously reported DIS-score range in dyskinetic CP (Monbaliu E et al., 2015). RESULTS: The motor phenotype was determined as: normal (n = 18/21), mildly impaired (reduced coordination (n = 2/21)) and abnormal (dyskinetic CP; n = 1/21). In absence of CP (n = 20/21), DIS-scores were lower (more favorable) than in dyskinetic CP, without any overlapping group scores (mean difference: 71 points; p < .05). However, the obtained DIS-scores were still higher than previously reported in healthy age-matched controls (mean difference: 14 points; p < .05). There was an association between DIS-scores and retrospective neonatal MRI (basal ganglia and thalamus injury on diffusion weighted imaging (DWI)) and (a)EEG parameters (p < .05). CONCLUSION: In the vast majority (95%) of Dutch TH-HIE treated pre-school children, the phenotypic motor outcome was favorable. However, DIS-scores were moderately increased compared with healthy age-matched controls. Future studies may elucidate the significance of moderately increased DIS-scores should to further extent.
Asunto(s)
Parálisis Cerebral/epidemiología , Parálisis Cerebral/prevención & control , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/terapia , Parálisis Cerebral/etiología , Niño , Preescolar , Discinesias/epidemiología , Discinesias/etiología , Discinesias/prevención & control , Femenino , Humanos , Recién Nacido , Masculino , Estudios RetrospectivosRESUMEN
GABAergic medium spiny neurons are the main neuronal population in the striatum. Calbindin is preferentially expressed in medium spiny neurons involved in the indirect pathway. The aim of the present work is to analyze the effect of perinatal asphyxia on different subpopulations of GABAergic neurons in the striatum and to assess the outcome of deep therapeutic hypothermia. The uterus of pregnant rats was removed by cesarean section and the fetuses were exposed to hypoxia by immersion in water (19 min) at 37°C (perinatal asphyxia). The hypothermic group was exposed to 10°C during 30 min after perinatal asphyxia. The rats were euthanized at the age of one month (adolescent/adult rats), their brains were dissected out and coronal sections were immunolabeled for calbindin, calretinin, NeuN, and reelin. Reelin+ cells showed no staining in the striatum besides subventricular zone. The perinatal asphyxia (PA) group showed a significant decrease in calbindin neurons and a paradoxical increase in neurons estimated by NeuN staining. Moreover, calretinin+ cells, a specific subpopulation of GABAergic neurons, showed an increase caused by PA. Deep hypothermia reversed most of these alterations probably by protecting calbindin neurons. Similarly, there was a reduction of the diameter of the anterior commissure produced by the asphyxia that was prevented by hypothermic treatment.
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Asfixia Neonatal/terapia , Cuerpo Estriado/patología , Discinesias/prevención & control , Hipotermia Inducida/métodos , Trastornos Psicóticos/prevención & control , Animales , Animales Recién Nacidos , Comisura Anterior Cerebral/patología , Encéfalo/metabolismo , Encéfalo/patología , Calbindina 2/metabolismo , Calbindinas/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Cuerpo Estriado/metabolismo , Discinesias/etiología , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Masculino , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Trastornos Psicóticos/etiología , Ratas , Ratas Sprague-Dawley , Proteína Reelina , Serina Endopeptidasas/metabolismoRESUMEN
Assessing patient goals is crucial in understanding patient centered outcomes and satisfaction. However, patient goals may change throughout treatment. Our objective is to identify the changes in patient-selected goals of Parkinson's disease (PD) patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and examine the relationship among patient-selected goal achievement, standard DBS outcome measures, and overall patient satisfaction. Seventy-five patients undergoing bilateral STN-DBS listed three patient-selected goals before surgery. After six months, patients were asked to restate the three goals and to rate the degree of goal achievement and the overall satisfaction of surgery. The three most frequently selected goals were "dyskinesia", "gait disorder", and "medication off duration". After six months, 80.0% of patients could not accurately recall their pre-DBS goals. "Dyskinesia" was the most consistently selected goal, more patients selected "tremor" and "less medication" at post-DBS compared to pre-DBS, and less patients selected "gait disorder" at post-DBS compared to pre-DBS. 74.7% of patients reported overall satisfaction by stating they were "very much" or "much better after surgery". Patient satisfaction significantly correlated with goal achievement (r = 0.640; p < 0.001). Interestingly, change in UPDRS motor scores did not correlate with patient satisfaction (r = 0.100; p = 0.395). Although recalled goals do not accurately represent the pre-surgical goals, the achievement score for recalled goals significantly correlated with patient satisfaction. Patient goals change due to many reasons. Therefore, follow-up patient counseling to discuss goals and outcomes is important in improving patient satisfaction after STN-DBS.
Asunto(s)
Estimulación Encefálica Profunda , Objetivos , Enfermedad de Parkinson/terapia , Satisfacción del Paciente , Núcleo Subtalámico/cirugía , Adulto , Anciano , Estimulación Encefálica Profunda/psicología , Discinesias/prevención & control , Discinesias/terapia , Femenino , Trastornos Neurológicos de la Marcha/prevención & control , Trastornos Neurológicos de la Marcha/terapia , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/cirugía , Resultado del Tratamiento , Temblor/prevención & control , Temblor/terapiaRESUMEN
Although Levodopa (l-DOPA), a dopamine precursor, exhibits a high risk of dyskinesia, it remains the primary treatment in Parkinson's disease (PD), a progressive neurodegenerative disorder. In this study, we designed poly(l-DOPA)-based self-assembled nanodrug (NanoDOPA) from amphiphilic block copolymer possessing poly(l-DOPA(OAc)2), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatment, the poly(l-DOPA(OAc)2) in the block copolymer was hydrolyzed to liberate l-DOPA gradually. Using the MPTP-induced PD mouse model, we observed that mice treated with NanoDOPA demonstrated a significant improvement of PD symptoms compared to the l-DOPA treatment. Interestingly, the NanoDOPA treatment did not cause the dyskinesia symptoms, which was clearly observed in the l-DOPA-treated mice. Furthermore, NanoDOPA exhibited remarkably lower toxicity in vitro compared to l-DOPA, in addition with no noticeable NanoDOPA toxicity observed in the treated mice. These results suggested that self-assembled NanoDOPA is a promising therapeutic in the treatment of PD. STATEMENT OF SIGNIFICANCE: In this study, we proposed a therapeutic approach for the effective treatment of Parkinson's disease (PD) using newly designed poly(l-DOPA)-based self-assembled nanodrug (NanoDOPA) prepared from amphiphilic block copolymers possessing poly(l-DOPA(OAc)2), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatments, NanoDOPA was hydrolyzed to liberate l-DOPA gradually, improving the pharmacokinetic value of l-DOPA. The mice treated with NanoDOPA significantly improved PD symptoms compared to the l-DOPA treatment in a neurotoxin-induced PD mouse model. Interestingly, NanoDOPA treatment did not cause dyskinesia symptoms, which was observed in the l-DOPA-treated mice. The obtained results in this study suggested that self-assembled NanoDOPA is a promising therapeutic in the treatment of PD.
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Discinesias/prevención & control , Indoles/uso terapéutico , Nanopartículas/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Polímeros/uso terapéutico , Animales , Bovinos , Línea Celular , Modelos Animales de Enfermedad , Dopamina , Indoles/síntesis química , Indoles/farmacocinética , Indoles/toxicidad , Levodopa/farmacocinética , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Nanopartículas/química , Nanopartículas/toxicidad , Polímeros/síntesis química , Polímeros/farmacocinética , Polímeros/toxicidadRESUMEN
Aldehyde dehydrogenase 1A1 (ALDH1A1), a retinoic acid (RA) synthase, is selectively expressed by the nigrostriatal dopaminergic (nDA) neurons that preferentially degenerate in Parkinson's disease (PD). ALDH1A1-positive axons mainly project to the dorsal striatum. However, whether ALDH1A1 and its products regulate the activity of postsynaptic striatal neurons is unclear. Here we show that µ-type opioid receptor (MOR1) levels were severely decreased in the dorsal striatum of postnatal and adult Aldh1a1 knockout mice, whereas dietary supplement of RA restores its expression. Furthermore, RA treatment also upregulates striatal MOR1 levels and signaling and alleviates L-DOPA-induced dyskinetic movements in pituitary homeobox 3 (Pitx3)-deficient mice that lack of ALDH1A1-expressing nDA neurons. Therefore, our findings demonstrate that ALDH1A1-synthesized RA is required for postsynaptic MOR1 expression in the postnatal and adult dorsal striatum, supporting potential therapeutic benefits of RA supplementation in moderating L-DOPA-induced dyskinesia.
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Familia de Aldehído Deshidrogenasa 1/fisiología , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Discinesias/prevención & control , Proteínas de Homeodominio/fisiología , Receptores Opioides mu/metabolismo , Retinal-Deshidrogenasa/fisiología , Factores de Transcripción/fisiología , Tretinoina/farmacología , Animales , Cuerpo Estriado/patología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Discinesias/etiología , Discinesias/metabolismo , Discinesias/patología , Femenino , Masculino , Ratones , Ratones Noqueados , Receptores Opioides mu/genéticaRESUMEN
RATIONALE: The respiratory effort index derived from vertical mandibular movements (MM-REI) is a potential marker of increased respiratory effort during sleep. We evaluated the effectiveness of mandibular advancement splint therapy using MM-REI, in comparison with the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). METHODS: Fifty-six subjects (median age, 47 years) with OSA treated with a custom mandibular advancement splint (Herbst appliance) were evaluated at the end of the titration procedure when snoring was reported absent by the sleep partner. We employed a magnetometer to capture mandibular movements (Brizzy; Nomics). Mandibular advancement splint efficacy was assessed as the percent change from baseline, using Bayesian multilevel models. RESULTS: At the end of titration, all indices of OSA severity decreased compared with baseline: AHI (-48.9% to -71.1%), ODI (-49.5% to -77.2%), with obstructive hypopnea index and MM-REI showing the largest responses (-70.6% to -88.5% and -69.5% to -96.3%, respectively). MM-REI normalization via reductions in both mandibular movement event rate and duration accurately reflected efficacy of the appliance. CONCLUSIONS: The reduction of vertical respiratory mandibular movements estimated by MM-REI and sleep respiratory effort duration accompanied the decrease in obstructive hypopneas, AHI, and ODI when snoring resolved in subjects with OSA treated with an optimally titrated mandibular advancement splint.
Asunto(s)
Discinesias , Mandíbula/fisiopatología , Avance Mandibular , Ferulas Oclusales , Apnea Obstructiva del Sueño , Ronquido , Discinesias/diagnóstico , Discinesias/fisiopatología , Discinesias/prevención & control , Femenino , Humanos , Hipoxia/etiología , Hipoxia/prevención & control , Magnetometría/métodos , Masculino , Avance Mandibular/instrumentación , Avance Mandibular/métodos , Persona de Mediana Edad , Respiración , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/terapia , Ronquido/etiología , Ronquido/fisiopatología , Ronquido/prevención & control , Resultado del TratamientoRESUMEN
Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden. If patients continue to experience off-time with functional impact on activities of daily living after best medication adjustments, implementation of infusion with apomorphine or levodopa, and surgical therapies should be considered. Presence of troublesome dyskinesia would also favor the choice of an advanced treatment. Compared with pulsatile oral therapy, both apomorphine and levodopa infusion determine more continuous striatal dopamine receptors stimulation than oral levodopa resulting in significant reduction of off-time and dyskinesia, particularly peak-dose, although not in their complete resolution. This observation proves that abnormal synaptic plasticity and connectivity changes cannot be reversed once they are established. Early implementation of these therapeutic strategies ideally would target patients as soon as motor complications begin rather than at late stage of advanced Parkinson's disease (PD) before dyskinesia have manifested. Preliminary evidence from early deep brain stimulation in patients with short disease duration and modest motor complications suggests that this approach can positively impact quality of life. It is conceivable that changing our PD treatment algorithm and implementing device-aided therapies at the beginning of the advanced phase before dyskinesia has established, will provide more stable motor conditions and longer functional autonomy.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Apomorfina/administración & dosificación , Discinesias/prevención & control , Infusiones Parenterales , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Discinesias/etiología , Humanos , Enfermedad de Parkinson/complicacionesRESUMEN
Impaired motor function, due to the dysfunction of the basal ganglia, is the most common syndrome of hepatic encephalopathy (HE), and its etiology remains poorly understood. Neural oxidative stress is shown to be the major cellular defects contributing to HE pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neurological disorders. We explored the neuroprotective role of UCP2 within the substantia nigra pars reticulate (SNr), the output structure of the basal ganglia, in HE. The toxin thioacetamide (TAA) induced HE mice showed hypolocomotion, which was associated with decreased ATP levels and loss of antioxidant substances SOD and GSH within the SNr. Stable overexpression of UCP2 via AAV-UCP2 under the control of the UCP2 promoter in bilateral SNr preserved local ATP level, increased antioxidant substances, and ameliorated locomotion defects after severe liver failure. Contrary to UCP2 overexpression, targeted knockdown of UCP2 within bilateral SNr via AAV-UCP2 shRNA exacerbated the impaired mitochondrial dysfunction and hypokinesia in HE mice. The modulatory effects of UCP2 was due to mediation of K+-Cl- cotransporter-2 (KCC2) expression on GABAergic neurons of SNr. Taken together, our results demonstrate that UCP2 exerts a neural protective role at the subcortical level by increasing the resistance of neurons to oxidative stress, which may offer a novel therapeutic target for the treatment of motor dysfunction diseases.
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Ganglios Basales/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Modelos Animales de Enfermedad , Discinesias/prevención & control , Proteína Desacopladora 2/administración & dosificación , Animales , Conducta Animal , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dependovirus/genética , Discinesias/etiología , Discinesias/metabolismo , Locomoción , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Tioacetamida/toxicidad , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismoRESUMEN
Tardive dyskinesia (TD) is a severe side effect of chronic neuroleptic treatment consisting of abnormal involuntary movements, characterized by orofacial dyskinesia (OD). Haloperidol (HAL)- induced OD has been widely used as an animal model to study the neuropathophysiology of human TD with its pathophysiology strongly associated with striatal oxidative stress. L-Theanine (LT), one of the major amino acid components in green tea, has potent antioxidative effects and is able to protect against various oxidative injuries. In this study, we examined the potential protective effects of LT on HAL-induced behavioral and neurochemical dysfunction in rats. HAL treatment (1 mg/kg i.p. for 21 days) induced significant increases (P < 0.001) in the frequency of vacuous chewing movement (VCM) and tongue protrusion (TP) as well as the duration of facial twitching (FT). LT treatment (100, 300 mg/kg orally for 35 days, starting 14 days before HAL injection) was able to prevent most of the HAL-induced OD. LT treatment was also able to reduce the lipid peroxidation (LPO) production, and enhance the antioxidation power in striatum from rats with HAL treatment. The above results indicate that LT has a protective role against HAL-induced OD, probably via its powerful antioxidative properties. Thus, LT may have a clinically relevant therapeutic effect in delaying or treating TD.
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Discinesias/prevención & control , Glutamatos/farmacología , Haloperidol/toxicidad , Discinesia Tardía/prevención & control , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Discinesia Tardía/inducido químicamenteRESUMEN
Typical antipsychotics, which are commonly used to treat schizophrenia, cause motor disorders such as tardive dyskinesia (TD) in humans and orofacial dyskinesia (OD) in rodents. The disease mechanisms as well as treatment effectiveness are still unknown. In this study, we investigated the effect of resveratrol, a polyphenol with neuroprotective properties, on behavioral changes induced by chronic treatment with fluphenazine in rats and the possible relationship between monoamine oxidase (MAO) activity and vacuous chewing movements (VCMs). Rats were treated for 18 weeks with fluphenazine enantate [25 mg/kg, intramuscularly (i.m.), every 21 days] and/or resveratrol (20 mg/kg, offered daily in drinking water). Next, body weight gain, behavioral parameters (VCMs and open field tests-locomotor and rearing activity), and MAO activity were evaluated. Fluphenazine treatment reduced body weight gain, number of crossings and rearings, and the co-treatment with resveratrol did not affect these alterations. Fluphenazine increased the prevalence and intensity of VCMs and the co-treatment with resveratrol reduced the VCMs. Furthermore, a negative correlation was found between the number of VCMs and MAO-B activity in the striatum of rats. Our data suggest that resveratrol could be promissory to decrease OD. Moreover, MAO-B activity in the striatum seems to be related to VCMs intensity.
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Antioxidantes/uso terapéutico , Antipsicóticos/toxicidad , Discinesias/prevención & control , Flufenazina/toxicidad , Actividad Motora/efectos de los fármacos , Estilbenos/uso terapéutico , Animales , Antioxidantes/farmacología , Antipsicóticos/administración & dosificación , Esquema de Medicación , Discinesias/psicología , Flufenazina/administración & dosificación , Masculino , Masticación/efectos de los fármacos , Masticación/fisiología , Actividad Motora/fisiología , Ratas , Ratas Wistar , Resveratrol , Estilbenos/farmacologíaRESUMEN
Adhesion is one of the most common postsurgical complications, occurring simultaneously as the damaged tissue heals. Accompanied by symptoms such as inflammation, pain and even dyskinesia in particular circumstances, tissue adhesion has substantially compromised the quality of life of patients. Instead of passive treatment, which involves high cost and prolonged hospital stay, active intervention to prevent the adhesion from happening has been accepted as the optimized strategy against this complication. Herein, this paper will cover not only the mechanism of adhesion forming, but also the biomaterials and medicines used in its prevention. Apart from acting as a direct barrier, biomaterials also show promising anti-adhesive bioactivity though their intrinsic physical and chemical are still not completely unveiled. Considering the diversity of human tissue organization, it is imperative that various biomaterials in combination with specific medicine could be tuned to fit the microenvironment of targeted tissues. With the illustration of different adhesion mechanism and solutions, we hope this review can become a beacon and further inspires the development of anti-adhesion biomedicines.
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Materiales Biocompatibles/administración & dosificación , Complicaciones Posoperatorias/prevención & control , Adherencias Tisulares/prevención & control , Animales , Discinesias/etiología , Discinesias/prevención & control , Humanos , Inflamación/etiología , Inflamación/prevención & control , Dolor/etiología , Dolor/prevención & control , Calidad de VidaRESUMEN
Effect of administration of Rice bran oil (RBO) was evaluated on haloperidol elicited tardive dyskinesia in rats. Albino Wistar rats treated with haloperidol in drinking water at a dose of 0.2mg/kg/day and RBO by oral tubes at a dose of 0.4 mL/day for 5 weeks. Motor coordination, VCMs and 8-hydroxy-2-(di-n-propylamino) tetraline)[8-OH-DPAT] _syndrome were monitored. Striatal serotonin (5-hydroxytryptamine; 5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels were determined by high performance liquid chromatography (HPLC-EC). Rats treated with haloperidol orally at a dose of for a period of 5 weeks developed VCMs, which increased progressively as the treatment continued for 5 weeks. Motor coordination impairment started after the 1st week and was maximally impaired after 3 weeks and gradually returned to the 1st week value. Co-administration of RBO prevented haloperidol_induced VCMs as well impairment of motor coordination. The intensity of 8-OH-DPAT_induced syndrome and decreased 5-HT metabolism were greater in water + haloperidol treated animals than RBO + haloperidol treated animals. The present study suggested that involvement of free radical in the development of TD and point to RBO as a possible therapeutic option to treat this hyperkinetic motor disorder.
Asunto(s)
Antipsicóticos/efectos adversos , Haloperidol/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Aceites de Plantas/uso terapéutico , Serotonina/metabolismo , Discinesia Tardía/prevención & control , 8-Hidroxi-2-(di-n-propilamino)tetralin/metabolismo , Animales , Discinesias/prevención & control , Ácido Hidroxiindolacético/metabolismo , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Equilibrio Postural/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Wistar , Aceite de Salvado de ArrozRESUMEN
Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.
Asunto(s)
Agmatina/administración & dosificación , Discinesias/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Reserpina/toxicidad , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Discinesias/prevención & control , Antagonistas de Aminoácidos Excitadores/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Óxido Nítrico Sintasa/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
We studied the interrelations between the activation of the receptors of musculoskeletal system and the spinal cord stimulation in the regulation of locomotor behavior in healthy subjects. We observed the effect of afferent stimulation on the patterns of stepping movements caused by percutaneous stimulation of spinal cord. It was found that the combination of percutaneous spinal cord stimulation and vibrostimulation increases the amplitude of leg movements. It was shown that the vibrostimulation of limb muscles at a frequency of less than 30 Hz may be used for comtrolling involuntary movements, caused by non-invasive stimulation of the spinal cord.
Asunto(s)
Estimulación Eléctrica , Movimiento , Músculo Esquelético/fisiología , Médula Espinal/fisiología , Discinesias/prevención & control , Electromiografía , Extremidades , Humanos , VibraciónRESUMEN
We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson's disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson's disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (± standard deviation) improvement in Unified Parkinson's Disease Rating Scale part III was 37 ± 11%, mean daily "off" period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily "on" time increased from 10.2 ± 3 to 13.7 ± 2 hours, "on" period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson's Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily "on" period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Carbidopa/administración & dosificación , Dopaminérgicos/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Desempeño Psicomotor/efectos de los fármacos , Calidad de Vida , Adulto , Anciano , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Australia , Duodeno , Discinesias/prevención & control , Femenino , Geles , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Estudios ProspectivosRESUMEN
OBJECTIVES: We wanted to investigate whether continuous intrajejunal levodopa-carbidopa intestinal gel (LCIG) therapy has an antidyskinetic effect in patients with Parkinson's disease (PD) and troublesome dyskinesias. We also sought to examine the effect of LCIG therapy on motor function and health-related quality of life (HRQoL). MATERIALS AND METHODS: This open-label pilot study used a single group pre-post design with follow-up at 6 months. Nine patients with PD who reported to spend at least 3 h per day in on with troublesome dyskinesia were included. The patients were examined at baseline using clinical and self-assessment measures and then switched from peroral/transdermal pharmacotherapy to LCIG therapy. Data collection was repeated 6 months after the pharmaceutical intervention. Nonparametric statistical methods were used for data analyses. RESULTS: The mean time spent in on with troublesome dyskinesia per day after 6 months of LCIG therapy decreased by 47% (P < 0.05). This observation was paralleled by a 112% increase in mean time spent in on without troublesome dyskinesia (P < 0.01). Patient self-assessment of dyskinesia intensity on the visual analog scale displayed a 90% reduction of mean dyskinesia intensity (P < 0.01) and patients also exhibited less dyskinesia during standardized levodopa tests. Furthermore, we noted improvements in motor function and HRQoL. CONCLUSIONS: In this pilot study, we found indications that LCIG therapy has a substantial antidyskinetic effect and could be an alternative also for PD patients with dyskinesias as a major symptom. However, further studies with blinded evaluation and larger numbers of patients are warranted to confirm the findings.