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PURPOSE: Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. METHODS: Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5 years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). RESULTS: Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. CONCLUSION: The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. TRIAL REGISTRATION: NCT02970526 (2016-11-22). https://classic. CLINICALTRIALS: gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .
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Antineoplásicos , Neoplasias Colorrectales , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico , Calidad de Vida , Humanos , Oxaliplatino/efectos adversos , Masculino , Femenino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Persona de Mediana Edad , Estudios Transversales , Anciano , Neoplasias Colorrectales/tratamiento farmacológico , Antineoplásicos/efectos adversos , Encuestas y Cuestionarios , Índice de Severidad de la Enfermedad , Trastornos Motores/inducido químicamente , Neuralgia/inducido químicamente , Adulto , Supervivientes de Cáncer/psicologíaRESUMEN
This review provides an up-to-date literature account on the efficacy of Botulinum toxin treatment for common motor disorders of Parkinson Disease. The reviewed disorders include the common motor disorders in PD such as tremor, focal foot dystonia, rigidity and freezing of gait (FOG). In the area of Parkinson tremor, two newly described evaluation/injection techniques (Yale method in USA and Western University method in Canada) offer efficacy with low incidence of hand and finger weakness as side effects. Blinded studies conducted on foot dystonia of PD indicate that botulinum toxin injections into toe flexors are efficacious in alleviating this form of dystonia. Small, blinded studies suggest improvement of Parkinson rigidity after botulinum toxin injection; proof of this claim, however, requires information from larger, blinded clinical trials. In FOG, the improvement reported in open label studies could not be substantiated in blinded investigations. However, there is room for further controlled studies that include the proximal lower limb muscles in the injection plan and/or use higher doses of the injected toxin for this indication.
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Toxinas Botulínicas Tipo A , Toxinas Botulínicas , Distonía , Trastornos Distónicos , Trastornos Neurológicos de la Marcha , Trastornos Motores , Enfermedad de Parkinson , Humanos , Toxinas Botulínicas/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Distonía/tratamiento farmacológico , Temblor/tratamiento farmacológico , Trastornos Motores/inducido químicamente , Trastornos Motores/complicaciones , Trastornos Motores/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Distónicos/tratamiento farmacológico , Toxinas Botulínicas Tipo A/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: The dorsal striatum is a brain area integrating information for movement output. The local field potentials (LFPs) reflect the neuronal activity that can be used for monitoring brain activities and controlling movement. MATERIALS AND METHODS: Rhythmic low gamma power activity (30.1-45 Hz) in the dorsal striatum was monitored according to voluntary motor movement in rotarod and bar tests in 0.5 mg/kg haloperidol-induced mice. RESULTS: Haloperidol can effectively induce movement impairment indicated by decreased low gamma LFP with the lessened rotarod test's latency fall, and the enhanced bar test's descending latency. L-DOPA was used for the induction of a dopamine-dependent signal. The results showed that 25 mg/kg of L-DOPA could reverse the effect of haloperidol by enhancing low gamma oscillation concomitantly with the improvement in behavioral movement as fast as 60 min after administration, suggesting that dopamine signaling increases low gamma frequency of LFP in correlation with the improved mice movement. This work supports quantitative LFP assessment as a monitoring tool to track drug action on the nervous system. CONCLUSION: In animal models of motor impairment, oral dopaminergic treatment can be effective in restoring motor dysfunction by stimulating low gamma power activity in the dorsal striatum.
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Dopamina , Trastornos Motores , Ratones , Animales , Levodopa , Haloperidol/efectos adversos , Trastornos Motores/inducido químicamente , Trastornos Motores/tratamiento farmacológico , EncéfaloRESUMEN
BACKGROUND: Behavioral disinhibition and motor impairment are both acutely elevated following alcohol consumption, and individual differences in sensitivity to alcohol-induced increases in these effects are associated with drinking habits. Specifically, high alcohol-induced disinhibition and low motor impairment have been identified as separate markers for alcohol-related problems. This study tested the degree to which alcohol-induced disinhibition and motor impairment jointly predict heavy drinking. We hypothesized that heavier drinkers would exhibit a combination of high sensitivity to alcohol-induced disinhibition and low sensitivity to its motor impairing effect. METHODS: Data from three studies were aggregated to comprise a sample of 96 young adults. Participants' motor coordination (grooved pegboard) and behavioral disinhibition (cued go/no-go) were assessed following consumption of 0.65 g/kg alcohol and a placebo during separate sessions. RESULTS: As BAC was ascending, alcohol increased motor impairment and disinhibition compared to placebo. Combined effects at this time of alcohol on motor impairment and disinhibition predicted typical drinking habits. Specifically, a combination of high sensitivity to alcohol's disinhibiting effect and low sensitivity to its motor impairing effect was associated with heavy drinking. As BAC was descending, only reduced sensitivity to motor impairment remained as a predictor of heavy drinking. CONCLUSIONS: The findings suggest that although motor impairment following alcohol consumption is associated with certain negative outcomes (e.g., increased risk for physical injury and motor vehicle accidents), such heightened motor impairment from alcohol may actually serve as a protective factor against the excessive drinking that can accompany the disinhibiting effect of alcohol.
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Trastornos Relacionados con Alcohol , Intoxicación Alcohólica , Trastornos Motores , Adulto Joven , Humanos , Factores Protectores , Trastornos Motores/inducido químicamente , Desempeño Psicomotor , Etanol , Consumo de Bebidas Alcohólicas/efectos adversosRESUMEN
Introduction: Dopamine replacement therapy with levodopa is the gold standard treatment of Parkinson's disease (PD); however long-term levodopa use is associated with abnormal involuntary movements known as levodopa-induced dyskinesia (LID) in most patients. LID is not preventable and represents the major limitation of PD treatment.Objective: This study was aimed to find clinical and behavioral features that could be used to identify, years in advance, PD patients that are at high risk of developing LID in the future. Method: Data from PD patients enrolled in The Parkinson's progression markers initiative (PPMI, Michael J. Fox Foundation) that developed dyskinesia during their participation in the study were compared with those who did not, and with healthy controls.Result: LID was preceded byhigher levels of trait anxiety and increased motor impairment in PD patients. Additionally, younger age at PD diagnosis, earlier need for dopaminergic therapy and higher initial levodopa dose, were associated with future development of dyskinesia.Conclusion: These findings suggest that easily detectable clinical and behavioral alterations may help to identify PD patients that are more susceptible to develop LID.
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Discinesia Inducida por Medicamentos , Trastornos Motores , Enfermedad de Parkinson , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/efectos adversos , Trastornos Motores/inducido químicamente , Trastornos Motores/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , Dopamina , Ansiedad/inducido químicamenteRESUMEN
Objectives: Honey contains phenolic acids and flavonoids, which are significant in developing drugs against neuroinflammation. The study was designed to evaluate the ameliorative potential of honey in lipopolysaccharides-induced neuroinflammation.Methods: Thirty male Wistar rats were divided into six groups, namely: the control group (10â mL/kg vehicle), the LPS only group (250â µg/kg), the honey (0.26, 0.31 and 0.36â g/kg) and the ibuprofen (100â mg/kg). LPS (250â µg/kg i.p) was administered for 7days followed by the treatment with honey and Ibuprofen for another 7days. Animals were assessed for memory impairment and anxiety levels using a Novel object recognition test (NORT), elevated plus maze (EPM), and open field test (OFT). Brain levels of pro-inflammatory cytokine level, acetylcholinesterase activity, and oxidative stress were determined. The neuronal alteration was assessed histologically using cresyl fast violet staining of the hippocampus, prefrontal cortex, and striatum.Results: Honey (0.31 and 0.36â g/kg) significantly ameliorated LPS-induced memory impairment on NORT and increased time spent in the open arm and increased the locomotor activity in the OFT. Honey significantly (p < 0.05) reduced LPS-induced elevation of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). It significantly reduced malondialdehyde and nitrite levels in mice brains and reversed depletion of reduced glutathione levels. Honey attenuated LPS-induced elevation of acetylcholinesterase activity in rat brains. Cresyl violet staining showed the restoration of neuronal organization and Nissl body distribution in the hippocampus, prefrontal cortex and striatum compared to the LPS only group.Discussion: Honey effectively ameliorated LPS-induced poor cognitive performance, anxiety, motor coordination responses to neuroinflammation, and oxidative stress.
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Ansiedad , Disfunción Cognitiva , Miel , Lipopolisacáridos , Trastornos de la Memoria , Trastornos Motores , Enfermedades Neuroinflamatorias , Lipopolisacáridos/farmacología , Ratas , Ratas Wistar , Masculino , Animales , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/prevención & control , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/prevención & control , Trastornos Motores/inducido químicamente , Trastornos Motores/prevención & control , Ansiedad/inducido químicamente , Ansiedad/prevención & control , Ibuprofeno/efectos adversos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/prevención & controlRESUMEN
We previously showed that a diet containing calcium carbonate causes impairments in spatial and recognition memory in mice. In this study, we investigated the effects of calcium carbonate supplementation on motor function. Motor function was determined using different tests that have been used to analyze different aspects of Parkinsonism. A catalepsy test for akinesia; a muscular strength assessment, pole test, beam-walking test, and gait analysis for motor coordination and balance assessment; and an open-field test for locomotor activity assessment were performed. The mice were fed diets containing 0.6% or 1.0% calcium carbonate for eight weeks, after which they were evaluated for motor functions. The diets containing calcium carbonate caused significant motor dysfunction, as revealed by the different tests, although the spontaneous locomotor activity did not change. Calcium carbonate supplementation decreased the dopamine content in the basal ganglia, including the striatum and substantia nigra, and the number of tyrosine hydroxylase-positive neurons in the substantia nigra. In addition, administration of L-dopa led to at least a partial recovery of motor dysfunction, suggesting that calcium carbonate supplementation causes motor dysfunction by decreasing the dopamine content in the basal ganglia. These results suggest that mice with calcium carbonate-induced motor dysfunction may be useful as a new animal model for Parkinson's disease and Huntington's disease.
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Carbonato de Calcio , Suplementos Dietéticos , Dopamina , Trastornos Motores , Animales , Carbonato de Calcio/efectos adversos , Suplementos Dietéticos/efectos adversos , Modelos Animales de Enfermedad , Ratones , Trastornos Motores/inducido químicamente , Enfermedad de Parkinson , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Maternal exposure to anesthetic agents could impose significant neurocognitive risks on the developing brain of infants. Myelin produced by oligodendrocytes (OLs) is essential for the development of brain. However, the concrete effect of general anesthesia on the development and myelination of OLs is still elusive. In this study, we aim to investigate postnatal myelination and neural behavior after maternal exposure to sevoflurane. Pregnant C57BL/6 J mice (gestational day 15.5) were anesthetized with 2.5% sevoflurane (in 97.5% O2) for 6 h. Cognitive function and motor coordination of the offspring mice were evaluated with novel object recognition, Morris water maze and accelerating rotarod tests. Myelination and development of hippocampal OLs were analyzed with immunohistochemistry, qRT-PCR, western blotting and electron microscopy. The functionality of myelin was measured with electrophysiology. Our results showed that sevoflurane anesthesia during the gestational period induced cognitive and motor impairments in offspring mice, accompanied with damages of myelin structure and down regulations of myelin-associated genes and proteins (including MBP, Olig1, PDGFRα, Sox10, etc.). The development and maturation of OLs were suppressed, and the axonal conduction velocity was declined. These results demonstrated that maternal sevoflurane exposure could induce detrimental effects on cognitive and motor functions in offspring, which might be associated with disrupted myelination of OLs in the hippocampus.
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Exposición Materna , Trastornos Motores , Animales , Cognición , Femenino , Hipocampo/metabolismo , Humanos , Exposición Materna/efectos adversos , Ratones , Ratones Endogámicos C57BL , Trastornos Motores/inducido químicamente , Vaina de Mielina , Oligodendroglía/fisiología , Embarazo , Sevoflurano/efectos adversosRESUMEN
Although serotonin 1A (5-HT1A) receptor agonists are widely used as the additive compound to reduce l-dopa-induced dyskinesia in Parkinson's disease (PD), few studies focused on the effect and mechanism of 5-HT1A receptor agonist on the motor symptoms of PD. Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were used and implantation of electrodes was performed in the motor cortex of these rats. So the effect of 5-HT1A receptor agonist 8-OH-DPAT on motor behaviors and oscillatory activities were evaluated. In addition, 8-OH-DPAT combined with D2 receptor antagonist raclopride, NMDA receptor antagonist MK-801, or its agonist d-cycloserine (DCS) were co-administrated. 8-OH-DPAT administration significantly improved spontaneous locomotor activity and asymmetric forepaw function in 6-OHDA-lesioned rats. Meanwhile, 8-OH-DPAT identified selective modulation of the abnormal high beta oscillations (25-40 Hz) in the motor cortex of 6-OHDA-lesioned rats, without inducing pathological finely tuned gamma around 80 Hz. Different from 8-OH-DPAT, l-dopa treatment produced a prolonged improvement on motor performances and differential regulation of high beta and gamma oscillations. However, dopamine D2 receptor antagonist had no influence on the 8-OH-DPAT-mediated-motor behaviors and beta oscillations in 6-OHDA-lesioned rats. In contrast, subthreshold NMDA receptor antagonist MK-801 obviously elevated the 8-OH-DPAT-mediated-motor behaviors, while NMDA receptor agonist DCS partially impaired the 8-OH-DPAT-mediated symptoms in 6-OHDA-lesioned rats. This study suggests that 5-HT1A receptor agonist 8-OH-DPAT improves motor activity and modulates the oscillations in the motor cortex of parkinsonian rats. Different from l-dopa, 8-OH-DPAT administration ameliorates motor symptoms of PD through glutamatergic rather than the dopaminergic pathway.
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Ritmo beta/fisiología , Corteza Motora/fisiología , Trastornos Parkinsonianos/fisiopatología , Receptor de Serotonina 5-HT1A/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/toxicidad , Animales , Ritmo beta/efectos de los fármacos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Corteza Motora/efectos de los fármacos , Trastornos Motores/inducido químicamente , Trastornos Motores/tratamiento farmacológico , Trastornos Motores/fisiopatología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT1/uso terapéuticoRESUMEN
Evidence suggests that exaggerated beta range local field potentials (LFP) in basal ganglia-thalamocortical circuits constitute an important biomarker for feedback for deep brain stimulation in Parkinson's disease patients, although the role of this phenomenon in triggering parkinsonian motor symptoms remains unclear. A useful model for probing the causal role of motor circuit LFP synchronization in motor dysfunction is the unilateral dopamine cell-lesioned rat, which shows dramatic motor deficits walking contralaterally to the lesion but can walk steadily ipsilaterally on a circular treadmill. Within hours after 6-OHDA injection, rats show marked deficits in ipsilateral walking with early loss of significant motor cortex (MCx) LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere; both effects were reversed by dopamine agonist administration. Increases in MCx and substantia nigra pars reticulata (SNpr) coherence and LFP power in the 29-40 Hz range emerged more gradually over 7 days, although without further progression of walking deficits. Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging over 7 days, as assessed during periods of walking before the morning treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. Earlier changes in cortical circuits, reflected in the rapid decreases in MCx LFP mid-gamma LFP activity, may contribute to evolving plasticity supporting increased beta range synchronized activity in basal ganglia-thalamocortical circuits after loss of dopamine receptor stimulation.
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Ritmo beta/fisiología , Ritmo Gamma/fisiología , Corteza Motora/fisiopatología , Trastornos Motores/fisiopatología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Animales , Ritmo beta/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/administración & dosificación , Prueba de Esfuerzo/métodos , Ritmo Gamma/efectos de los fármacos , Masculino , Corteza Motora/efectos de los fármacos , Trastornos Motores/inducido químicamente , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Long-Evans , Receptores de Dopamina D1/antagonistas & inhibidoresRESUMEN
Tumour necrosis factor-α (TNF-α), a crucial cytokine, has various homeostatic and pathogenic bioactivities. The aim of this study was to assess the neuroprotective effect of ketamine against TNF-α-induced motor dysfunction and neuronal necroptosis in male C57BL/6J mice in vivo and HT-22 cell lines in vitro. The behavioural testing results of the present study indicate that ketamine ameliorated TNF-α-induced neurological dysfunction. Moreover, immunohistochemical staining results showed that TNF-α-induced brain dysfunction was caused by necroptosis and microglial activation, which could be attenuated by ketamine pre-treatment inhibiting reactive oxygen species production and mixed lineage kinase domain-like phosphorylation in hippocampal neurons. Therefore, we concluded that ketamine may have neuroprotective effects as a potent inhibitor of necroptosis, which provides a new theoretical and experimental basis for the application of ketamine in TNF-α-induced necroptosis-associated diseases.
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Hipocampo/efectos de los fármacos , Ketamina/farmacología , Trastornos Motores/tratamiento farmacológico , Necrosis/tratamiento farmacológico , Neuronas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Línea Celular , Supervivencia Celular , Hipocampo/patología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Modelos Animales , Trastornos Motores/inducido químicamente , Necrosis/inducido químicamente , Necrosis/patología , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológicoRESUMEN
AIMS: Experimental and clinical evidences demonstrate that common dysregulated pathways are involved in Parkinson's disease (PD) and type 2 diabetes. Recently, insulin treatment through intranasal (IN) approach has gained attention in PD, although the underlying mechanism of its potential therapeutic effects is still unclear. In this study, we investigated the effects of insulin treatment in a rat model of PD with emphasis on mitochondrial function indices in striatum. METHODS: Rats were treated with a daily low dose (4IU/day) of IN insulin, starting 72 h after 6-OHDA-induced lesion and continued for 14 days. Motor performance, dopaminergic cell survival, mitochondrial dehydrogenases activity, mitochondrial swelling, mitochondria permeability transition pore (mPTP), mitochondrial membrane potential (Δψm ), reactive oxygen species (ROS) formation, and glutathione (GSH) content in mitochondria, mitochondrial adenosine triphosphate (ATP), and the gene expression of PGC-1α, TFAM, Drp-1, GFAP, and Iba-1 were assessed. RESULTS: Intranasal insulin significantly reduces 6-OHDA-induced motor dysfunction and dopaminergic cell death. In parallel, it improves mitochondrial function indices and modulates mitochondria biogenesis and fission as well as activation of astrocytes and microglia. CONCLUSION: Considering the prominent role of mitochondrial dysfunction in PD pathology, IN insulin as a disease-modifying therapy for PD should be considered for extensive research.
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Insulina/administración & dosificación , Mitocondrias/efectos de los fármacos , Trastornos Motores/tratamiento farmacológico , Oxidopamina/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Administración Intranasal , Animales , Humanos , Masculino , Mitocondrias/fisiología , Trastornos Motores/inducido químicamente , Trastornos Motores/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , RotaciónRESUMEN
Marijuana or synthetic cannabinoids and alcohol are often used together, with these combinations causing motor impairments that can subsequently lead to motor vehicle accidents. This study investigated the combined use of both synthetic cannabinoids and ethanol and their effect on motor coordination in mice in addition to examining the neurochemical changes in the cerebellum. Ethanol (2 g/kg, i.p.) significantly induced motor impairment in the accelerating rotarod test in mice. Furthermore, ethanol-induced motor impairments were further accentuated when combined with the synthetic cannabinoid, JWH-018 or AB-CHMINACA. The enhancement effects of the synthetic cannabinoids were completely antagonized by pretreatment with the selective CB1 receptor antagonist AM251, but not by the selective CB2 receptor antagonist AM630. Neurochemical study results showed that ethanol caused a reduction in the extracellular glutamate levels in the cerebellum during periods of ethanol-induced motor impairment. In addition to the enhanced motor impairment seen when ethanol was combined with JWH-018, these combinations also enhanced the reduction of the extracellular glutamate levels in the cerebellum. We additionally used microelectrode array recordings to examine the effects of ethanol and/or JWH-018 on the spontaneous network activity in primary cultures from mouse cerebellum. Results showed that ethanol combined with JWH-018 significantly reduced spontaneous neuronal network activity in the primary cerebellar culture. Our findings demonstrate that ethanol-induced motor impairments are enhanced by synthetic cannabinoids, with these effects potentially mediated by CB1 receptors. An accentuated reduction of neurotransmissions in the cerebellum may play an important role in motor impairments caused by ethanol combined with synthetic cannabinoids.
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Cannabinoides/toxicidad , Etanol/toxicidad , Ácido Glutámico/metabolismo , Indazoles/toxicidad , Indoles/toxicidad , Trastornos Motores/inducido químicamente , Naftalenos/toxicidad , Transmisión Sináptica/efectos de los fármacos , Valina/análogos & derivados , Animales , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Cerebelo/fisiología , Sinergismo Farmacológico , Masculino , Ratones Endogámicos ICR , Trastornos Motores/metabolismo , Trastornos Motores/fisiopatología , Valina/toxicidadRESUMEN
In Parkinson's disease (PD) reduced levels of dopamine (DA) in the striatum lead to an abnormal circuit activity of the basal ganglia and an increased output through the substantia nigra pars reticulata (SNr) and the globus pallidus internal part. Synaptic inputs to the SNr shape its activity, however, the properties of glutamatergic synaptic transmission in this output nucleus of the basal ganglia in control and DA-depleted conditions are not fully elucidated. Using whole-cell patch-clamp recordings and pharmacological tools, we examined alterations in glutamatergic synaptic transmission in the SNr of a mouse model of PD, i.e. mice with unilateral 6-OHDA lesion of DA neurons in the substantia nigra pars compacta, as compared to control mice. We found that AMPA receptor (AMPAR)-mediated spontaneous and evoked excitatory postsynaptic currents (sEPSCs and eEPSCs) were not altered. The AMPA/NMDA ratio was significantly decreased in 6-OHDA-lesioned mice, suggesting an increased synaptic function of NMDA receptors (NMDARs) in DA-depleted mice. The decay kinetics of NMDAR-eEPSCs were faster in 6-OHDA-lesioned mice, indicating a possible change in the subunit composition of synaptic NMDARs. In control mice NMDAR-eEPSCs were mediated by diheteromeric NMDARs made of GluN2A, GluN2B and GluN2D. In 6-OHDA-lesioned mice the function of diheteromeric NMDARs containing either GluN2B or GluN2D was dramatically decreased, whereas the function of diheteromeric NMDARs made of GluN2A was preserved. Microinjections of an NMDAR antagonist into the SNr of 6-OHDA-lesioned mice resulted in significant improvements in spontaneous locomotion. This study identifies novel alterations occurring at excitatory synapses in the basal ganglia output nucleus following DA depletion. An increased synaptic NMDAR function, due to an altered subunit composition, might contribute to hyperactivation of SNr neurons in the DA depleted state and to motor impairments in PD.
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Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/metabolismo , Porción Reticular de la Sustancia Negra/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Sustancia Negra/metabolismo , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Motores/inducido químicamente , Trastornos Motores/tratamiento farmacológico , Trastornos Motores/metabolismo , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been developed not only to better understand the mechanisms underlying neurodegeneration but also to test the potential of emerging disease-modifying therapies. However, despite aging being the main risk factor for developing idiopathic PD, most of the studies do not use aged animals. Therefore, this study aimed at assessing the effect of aging in the unilateral 6-hydroxydopamine (6-OHDA)-induced animal model of PD. For this, female young adult and aged rats received a unilateral injection of 6-OHDA into the medial forebrain bundle. Subsequently, the impact of aging on 6-OHDA-induced effects on animal welfare, motor performance, and nigrostriatal integrity were assessed. The results showed that aging had a negative impact on animal welfare after surgery. Furthermore, 6-OHDA-induced impairments on skilled motor function were significantly higher in aged rats when compared with their younger counterparts. Nigrostriatal histological analysis further revealed an increased 6-OHDA-induced dopaminergic cell loss in the SNpc of aged animals when compared to young animals. Overall, our results demonstrate a higher susceptibility of aged animals to 6-OHDA toxic insult.
Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Enfermedad de Parkinson Secundaria/fisiopatología , Enfermedad de Parkinson/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Femenino , Humanos , Masculino , Trastornos Motores/inducido químicamente , Trastornos Motores/metabolismo , Trastornos Motores/patología , Oxidopamina/toxicidad , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Ratas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
The motor features in Parkinson's disease (PD) are associated with the degeneration of dopaminergic cells in the substantia nigra in the brain. Thus, the gold-standard in PD therapeutics still consists of dopamine replacement with levodopa. However, as the disease progresses, this therapeutic option becomes less effective and can be accompanied by levodopa-induced complications. On the other hand, several other neuronal pathways have been implicated in the pathological mechanisms of PD. In this context, the development of alternative therapeutic options that modulate non-dopaminergic targets is emerging as a major goal in the field. In a phenotypic-based screen in a zebrafish model of PD, we identified tapentadol as a candidate molecule for PD. The therapeutic potential of an agent that modulates the opioid and noradrenergic systems has not been explored, despite the implication of both neuronal pathways in parkinsonism. Therefore, we assessed the therapeutic properties of this µ-opioid receptor agonist and norepinephrine reuptake inhibitor in the 6-hydroxydopamine mouse model of parkinsonism. We further submitted 6-hydroxydopamine-lesioned mice to chronic treatment with levodopa and evaluated the effects of tapentadol during levodopa OFF states and on levodopa-induced dyskinesia. Importantly, we found that tapentadol halted the aggravation of dyskinesia and improved the motor impairments during levodopa OFF states. Altogether, our findings raise the hypothesis that concomitant modulation of µ-opioid receptor and norepinephrine transporter might constitute relevant intervention strategies in PD and that tapentadol holds therapeutic potential that may be translated into the clinical practice.
Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/prevención & control , Trastornos Motores/prevención & control , Trastornos Parkinsonianos/prevención & control , Tapentadol/uso terapéutico , Animales , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/toxicidad , Masculino , Ratones , Trastornos Motores/inducido químicamente , Trastornos Motores/fisiopatología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatologíaRESUMEN
Gait analysis is used to quantify changes in motor function in many rodent models of disease. Despite the importance of assessing gait and motor function in many areas of research, the available commercial options have several limitations such as high cost and lack of accessible, open code. To address these issues, we developed PrAnCER, Paw-Print Analysis of Contrast-Enhanced Recordings, for automated quantification of gait. The contrast-enhanced recordings are produced by using a translucent floor that obscures objects not in contact with the surface, effectively isolating the rat's paw prints as it walks. Using these videos, our simple software program reliably measures a variety of spatiotemporal gait parameters. To demonstrate that PrAnCER can accurately detect changes in motor function, we employed a haloperidol model of Parkinson's disease (PD). We tested rats at two doses of haloperidol: high dose (0.30 mg/kg) and low dose (0.15 mg/kg). Haloperidol significantly increased stance duration and hind paw contact area in the low dose condition, as might be expected in a PD model. In the high dose condition, we found a similar increase in contact area but also an unexpected increase in stride length. With further research, we found that this increased stride length is consistent with the bracing-escape phenomenon commonly observed at higher doses of haloperidol. Thus, PrAnCER was able to detect both expected and unexpected changes in rodent gait patterns. Additionally, we confirmed that PrAnCER is consistent and accurate when compared with manual scoring of gait parameters.
Asunto(s)
Análisis Costo-Beneficio/métodos , Análisis de la Marcha/métodos , Marcha/fisiología , Trastornos Motores/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Grabación en Video/métodos , Animales , Análisis Costo-Beneficio/economía , Marcha/efectos de los fármacos , Haloperidol/toxicidad , Masculino , Trastornos Motores/inducido químicamente , Trastornos Motores/economía , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/economía , Ratas , Programas Informáticos/economía , Grabación en Video/economíaRESUMEN
Tract tracing with neuronal tracers not only represents a straightforward approach to identify axonal projection connection between regions of the nervous system at distance but also provides compelling evidence for axonal regeneration. An ideal neuronal tracer meets certain criteria including high labeling efficacy, minimal neurotoxicity, rapid labeling, suitable stability in vivo, and compatibility to tissue processing for histological/immunohistochemical staining. Although labeling efficacy of commonly used fluorescent tracers has been studied extensively, neurotoxicity and their effect on neural functions remains poorly understood. In the present study, we comprehensively evaluated motor and sensory nerve function 2-24 weeks after injection of retrograde tracer Fluoro-Gold (FG), True Blue (TB) or Fluoro-Ruby (FR) in the tibial nerve in adult Spague-Dawley rats. We found that motor and sensory nerve functions were completely recovered by 24 weeks after tracer exposure, and that FG lead to a more prolonged delay in functional recovery than TB. These findings shed light on the long-term effect of tracers on nerve function and peripheral axonal regeneration, and therefore have implications in selection of appropriate tracers in relevant studies.
Asunto(s)
Dextranos/administración & dosificación , Trastornos Motores/patología , Atrofia Muscular/patología , Regeneración Nerviosa , Rodaminas/administración & dosificación , Células Receptoras Sensoriales/patología , Nervio Tibial/patología , Animales , Dextranos/efectos adversos , Masculino , Trastornos Motores/inducido químicamente , Atrofia Muscular/inducido químicamente , Ratas , Ratas Sprague-Dawley , Rodaminas/efectos adversos , Células Receptoras Sensoriales/efectos de los fármacos , Nervio Tibial/efectos de los fármacos , Nervio Tibial/lesionesRESUMEN
BACKGROUND: Midazolam has been found to exacerbate or unmask limb motor dysfunction in patients with brain tumors. This study aimed to determine whether the exacerbated upper limb motor-sensory deficits are mediated through benzodiazepine sites by demonstrating reversibility by flumazenil in patients with gliomas in eloquent areas. METHODS: This was an interventional, parallel assignment, nonrandomized trial. Study subjects were admitted in the operating room. Patients with supratentorial eloquent area gliomas and volunteers of similar age without neurologic disease were sedated with midazolam, but still responsive and cooperative. Motor and sensory functions for upper extremities were evaluated by the Nine-Hole Peg Test before and after midazolam, as well as after flumazenil reversal. RESULTS: Thirty-two cases were included: 15 in the glioma group and 17 in the control group. The total dose of midazolam and flumazenil were comparable between the groups. In the glioma group, the times to task completion after midazolam in the contralateral hand (P = 0.001) and ipsilateral hand (P = 0.002) were 26.5 (95% CI, 11.3 to 41.7) and 13.7 (95% CI, 5.0 to 22.4) seconds slower than baseline, respectively. After flumazenil reversal, the contralateral hand (P = 0.99) and ipsilateral hand (P = 0.187) performed 1.2 (95% CI, -3.3 to 5.8) and 1.5 (95% CI, -0.5 to 3.5) seconds slower than baseline, respectively. In the control group, the dominant (P < 0.001) and nondominant hand (P = 0.006) were 2.9 (95% CI, 1.4 to 4.3) and 1.7 (95% CI, 0.5 to 2.9) seconds slower than baseline, respectively. After flumazenil, the dominant hand (P = 0.99) and nondominant hand (P = 0.019) performed 0.2 (95% CI, -0.7 to 1.0) and 1.3 (95% CI, -0.2 to 2.4) seconds faster than baseline, respectively. CONCLUSIONS: In patients with eloquent area gliomas, mild sedation with midazolam induced motor coordination deficits in upper limbs. This deficit was almost completely reversed by the benzodiazepine antagonist flumazenil, suggesting that this is a reversible abnormality linked to occupation of the receptor by midazolam.
Asunto(s)
Neoplasias Encefálicas/fisiopatología , Flumazenil/farmacología , Glioma/fisiopatología , Midazolam/farmacología , Trastornos Motores/tratamiento farmacológico , Extremidad Superior/fisiopatología , Adulto , Neoplasias Encefálicas/complicaciones , Femenino , Moduladores del GABA/farmacología , Glioma/complicaciones , Humanos , Hipnóticos y Sedantes/farmacología , Masculino , Persona de Mediana Edad , Trastornos Motores/inducido químicamente , Trastornos Motores/fisiopatologíaRESUMEN
The striatum plays a critical role in motor control and also learning and memory of motor skills. It has been reported that striatal synaptic components are significantly decreased in dopaminergic-denervated striatum. In this study the effects of apelin-13 were investigated on motor disorders and striatal synaptosomal expression of PSD-95, neurexin1, neuroligin, metabotropic glutamate receptor (mGlu R1) and dopaminergic receptors (DR1 and DR2) in rat parkinsonism experimental model. 6-hydroxydopamine (6-OHDA) was injected into the substantia nigra. Apelin-13 (1, 2 and 3 µg/rat) was administered into the substantia nigra one week after the 6-OHDA injection. Accelerating rotarod, beam-balance, beam-walking and bar tests were performed one month after the apelin injection. Immunohistochemistry staining of dopaminergic neurons was performed. The levels of synaptic proteins were determined by immunoblotting. 6-OHDA-treated animals showed a significant impairment in motor-skill tasks and a dramatically change in the expression levels of mentioned proteins. Apelin-13 (3 µg/rat) significantly attenuates the motor impairments and prevents the changes in striatal synaptic elements in 6-OHDA-treated animals. In addition, it could rescue the dopaminergic neurons of the substantia nigra. The data will potentially extend the possible benefic aspect of apelin in neurodegenerative disorders.