RESUMEN
Recent studies suggest that impaired glutathione synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we investigated the influence of repeated co-treated with mirtazapine and aripiprazole on the schizophrenia-like behavior and brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Between the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12909 alone or in combination. Mirtazapine and aripiprazole were given repeatedly, once daily for 21 days before the tests. The behavioral and biochemical tests were performed in p90-92 rats. BSO given alone and in combination with GBR 12909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with an ineffective dose of aripiprazole and mirtazapine also abolished the behavioral deficits and biochemical changes, especially in the hippocampus in these rats. The present study indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioural and biochemical deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with an ineffective dose of aripiprazole and mirtazapine. The above data suggest that this neurodevelopment rat model of schizophrenia-induced by glutathione deficit evoked by repeated treatment with BSO alone and together with GBR 12909 in early postnatal life may be useful for studies on the pathomechanism of schizophrenia.
Asunto(s)
Esquizofrenia , Animales , Aripiprazol/farmacología , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Glutatión , Masculino , Mirtazapina , ARN Mensajero , Ratas , Ratas Sprague-Dawley , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
OBJECTIVES: To investigate a possible association between isolated white matter lesions suggestive of demyelinating disease in magnetic resonance imaging (MRI) and patent foramen ovale (PFO) evidence in migraine patients, with or without aura. MATERIALS: 31 migraine patients, 28 females and 3 males, with MRI evidence of white matter lesions suggestive of demyelinating disease according to the Barkhof Criteria. All patients underwent further diagnostics including lumbar puncture, autoimmunity panel and cardiological evaluation to detect the presence of PFO. The mean duration of follow-up was 3.46â¯years and MIPAV software was used to analyze MRI imaging. RESULTS: 14 of the 31 patients (45%) had PFO. A significant association was found between PFO and migraine with visual aura (pâ¯<â¯0.001). No difference in lesion number, volume or area between patients with and without PFO was found, but the distribution was mainly occipital (pâ¯<â¯0.001) in patients with PFO. The follow-up showed a stationary lesion load in all PFO patients; no infratentorial or spinal cord lesion and no enhancement or corpus callosum lesion was ever detected. At the end of follow-up four patients developed multiple sclerosis: younger age at first MRI and oligoclonal bands were associated risk factors. CONCLUSIONS: Migraine is often one of the main symptoms leading to MRI, and in many cases white matter lesions of unspecific significance are discovered, thus placing demyelinating diseases in the differential diagnosis. Our study underlines the potential pathogenetic role of PFO in generating white matter lesions in migraine patients (45%), particularly those with visual aura and occipital lesions. For this reason, we affirm that PFO represents a cardinal point in the differential diagnosis of suspected demyelinating disease.
Asunto(s)
Enfermedades Desmielinizantes/diagnóstico , Foramen Oval Permeable/diagnóstico , Migraña con Aura/diagnóstico , Adulto , Encéfalo/diagnóstico por imagen , Enfermedades Desmielinizantes/complicaciones , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Foramen Oval Permeable/complicaciones , Corazón/diagnóstico por imagen , Humanos , Masculino , Migraña con Aura/complicaciones , Migraña sin Aura/complicaciones , Migraña sin Aura/diagnóstico , Bandas Oligoclonales/líquido cefalorraquídeo , Estudios Retrospectivos , Médula Espinal/diagnóstico por imagenRESUMEN
The proteasome inhibition and mitochondrial dysfunction are involved in pathomechanism of Parkinson's disease. The main aim of this study was to assess how particular culture conditions of human dopaminergic neuroblastoma SH-SY5Y cells could affect the extent of neurodegeneration induced by proteasome inhibitor-lactacystin (LC) and mitochondrial toxin-rotenone (Rot). This study revealed that induction of neuronal differentiation of SH-SY5Y cells with retinoic acid (RA-SH-SY5Y) caused a higher resistance of these cells to LC-evoked cell death when compared to undifferentiated cells (UN-SH-SY5Y). In contrast, RA-SH-SY5Y cells were more vulnerable than the UN-SH-SY5Y to Rot-induced cell damage. Furthermore, we found that a prolonged incubation of the cells under low serum condition (PLSC) significantly increased the LC toxicity in both differentiated and undifferentiated cells. Next, the effects of combined treatment with LC and Rot on cell viability were studied in RA-SH-SY5Y cells under PLSC and normal low serum condition (NLSC). At a low concentration, Rot (0.001-1 µM) attenuated the LC-evoked cell death in RA-SH-SY5Y cells exposed to NLSC. In contrast, under PLSC low concentrations of Rot lacked neuroprotective action while its higher levels (10 µM) enhanced the LC toxicity. Further, we showed that low concentrations of celastrol (Cel; 0.001 µM), a putative neuroprotective agent with antioxidant and anti-inflammatory properties, were able to partially attenuate the Rot-evoked toxicity under both PLSC and NLSC. On the other hand, Cel (0.001 and 0.01 µM) attenuated the LC-induced cell damage only under PLSC. Interestingly, higher concentrations of Cel (>1 µM) reduced cell viability in both UN- and RA-SH-SY5Y but only in UN-SH-SY5Y cells the effect was enhanced under PLSC. The obtained data indicate that toxicity of LC and Rot in SH-SY5Y cell line depends on the stage of cell differentiation and is enhanced in cells cultured for a longer time in low serum medium. Moreover, the neuroprotective properties of Rot and Cel against the LC-induced cell damage can be observed only under particular low serum conditions.
Asunto(s)
Acetilcisteína/análogos & derivados , Medio de Cultivo Libre de Suero , Degeneración Nerviosa/inducido químicamente , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/fisiopatología , Rotenona/toxicidad , Tretinoina/farmacología , Acetilcisteína/antagonistas & inhibidores , Acetilcisteína/toxicidad , Muerte Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Degeneración Nerviosa/prevención & control , Triterpenos Pentacíclicos , Rotenona/antagonistas & inhibidores , Factores de Tiempo , Triterpenos/farmacologíaRESUMEN
The dysfunction of the proteasome system is implicated in the pathomechanism of several chronic neurodegenerative diseases. Lactacystin (LC), an irreversible proteasome inhibitor, induces cell death in primary cortical neurons, however, the molecular mechanisms of its neurotoxic action has been only partially unraveled. In this study we aimed to elucidate an involvement of the key enzymatic pathways responsible for LC-induced neuronal cell death. Incubation of primary cortical neurons with LC (0.25-50 µg/ml) evoked neuronal cell death in concentration- and time-dependent manner. Lactacystin (2.5 µg/ml; 6.6µM) enhanced caspase-3 activity, but caspase-3 inhibitor, Ac-DEVD-CHO did not attenuate the LC-evoked cell damage. Western blot analysis showed a time-dependent, prolonged activation of MAPK/ERK1/2 pathway after LC exposure. Moreover, inhibitors of MAPK/ERK1/2 signaling, U0126 and PD98052 attenuated the LC-evoked cell death. We also found that LC-treatment resulted in the induction of calpains and calpain inhibitors (MDL28170 and calpeptin) protected neurons against the LC-induced cell damage. Neuroprotective action of MAPK/ERK1/2 and calpain inhibitors were connected with attenuation of LC-induced DNA fragmentation measured by Hoechst 33342 staining and TUNEL assay. However, only MAPK/ERK1/2 but not calpain inhibitors, attenuated the LC-induced AIF (apoptosis inducing factor) release. Further studies showed no synergy between neuroprotective effects of MAPK/ERK1/2 and calpain inhibitors given in combination when compared to their effects alone. The obtained data provided evidence for neuroprotective potency of MAPK/ERK1/2 and calpain, but not caspase-3 inhibition against the neurotoxic effects of LC in primary cortical neurons and give rationale for using these inhibitors in the treatment of neurodegenerative diseases connected with proteasome dysfunction.
Asunto(s)
Acetilcisteína/análogos & derivados , Calpaína/antagonistas & inhibidores , Corteza Cerebral/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/toxicidad , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Acetilcisteína/toxicidad , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Butadienos/farmacología , Calpaína/metabolismo , Caspasa 3/metabolismo , Inhibidores de Caspasas , Células Cultivadas , Corteza Cerebral/embriología , Corteza Cerebral/enzimología , Corteza Cerebral/patología , Citoprotección , Dipéptidos/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática , Edad Gestacional , Etiquetado Corte-Fin in Situ , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neuronas/enzimología , Neuronas/patología , Nitrilos/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Transducción de Señal/efectos de los fármacos , Espectrina/metabolismo , Factores de TiempoRESUMEN
The contribution of (R)-enantiomer of N-methyl-salsolinol (1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; NMSal) to the degeneration of dopaminergic neurons in the course of Parkinson's disease (PD) has been predominantly suggested by in vitro experiments in cell culture and by an in vivo study in which this compound has been directly injected into the rat striatum. The aim of the present study was to examine the effects of racemic NMSal (50 and 100 mg/kg) administered systemically, acutely and chronically for 21 days to rats, on the neurochemical and behavioral markers of PD. Our results showed that racemic NMSal easily penetrated the blood-brain barrier. Its brain level was relatively high 2-6 h after a single injection than gradually decreased. NMSal was quickly eliminated from the rat brain, its concentration 24 h after withdrawal from chronic treatment was very low. NMSal at both examined doses did not affect striatal and nigral levels of dopamine (DA) 2 h after the first and last chronic injections, however, it markedly changed DA catabolism. In the striatum both its doses evoked a significant acceleration of the total and oxidative, monoamine oxidase (MAO)-dependent DA catabolism without affecting the catechol-O-methyltransferase (COMT)-dependent O-methylation. In the substantia nigra (SN), only the higher dose of NMSal produced such effect. DA catabolism in either structure was the same as in control 24 h after cessation of chronic treatment. The second characteristic marker of PD, the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SN, was not affected by chronic NMSal treatment as revealed by the stereological counting. In the behavioral study, it was found that racemic NMSal significantly suppressed spontaneous locomotor activity and effectively prevented that stimulated by apomorphine. Our results suggest that NMSal may play an important role in the regulation of dopaminergic activity rather than in inducing changes of parkinsonian type.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Sustancia Negra/efectos de los fármacos , Tetrahidroisoquinolinas/administración & dosificación , Anfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Inhibidores de Captación de Dopamina/farmacología , Esquema de Medicación , Interacciones Farmacológicas , Electromiografía , Masculino , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/ultraestructura , Actividad Motora/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/ultraestructura , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/fisiopatología , Sustancia Negra/fisiología , Tetrahidroisoquinolinas/metabolismo , Factores de Tiempo , Distribución Tisular , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Antioxidative properties of alpha-lipoic acid (LA) are widely investigated in different in vivo and in vitro models. The aim of this study was to examine whether LA attenuates oxidative stress induced in rats by reserpine, a model substance frequently used to produce Parkinsonism in animals. Male Wistar rats were treated with reserpine (5 mg/kg) and LA (50 mg/kg) separately or in combination. The levels of reduced glutathione (GSH), glutathione disulfide (GSSG), nitric oxide (NO) and S-nitrosothiols as well as activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and L-gamma-glutamyl transpeptidase (gamma-GT) were determined in the striatum and prefrontal cortex homogenates. In the striatum and prefrontal cortex a single dose of reserpine significantly enhanced levels of GSSG and NO but not that of S-nitrosothiols when compared with control. In the striatum, LA administered jointly with reserpine markedly increased the concentration of GSH and decreased GSSG level. In the prefrontal cortex, such treatment produced only an increasing tendency in GSH level but caused no changes in GSSG content. In both structures LA injected jointly with reserpine markedly decreased NO concentrations but did not cause significant changes in S-nitrosothiol levels when compared with control. Enzymatic activities of GPx and GST were intensified by LA in the striatum. In the prefrontal cortex, GPx activity was not altered, while that of GST was decreased. Gamma-GT activity was attenuated by reserpine in the striatum while LA reversed this effect. Such changes were not observed in the prefrontal cortex. The mode of LA action in the striatum during the reserpine-evoked oxidative stress strongly suggests that this compound may be of therapeutic value in the treatment of Parkinson's disease.
Asunto(s)
Antioxidantes/farmacología , Antipsicóticos/farmacología , Cuerpo Estriado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Reserpina/farmacología , Ácido Tióctico/farmacología , Animales , Química Encefálica/efectos de los fármacos , Interacciones Farmacológicas , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratas , Ratas WistarRESUMEN
The causes of neurodegeneration are not well understood. However, the role of environmental and endogenous toxins is receiving much attention. In this study, we compared the synthetic neurotoxin 1-methyl-4-phenyl-pyridinium with beta-carbolines occurring in human brain. Methylation of both nitrogens is necessary to convert a beta-carboline into a potent inhibitor of mitochondrial complex I. The respective beta-carboline, 2,9-dimethyl-beta-carbolinium ion is neurotoxic in rats. To investigate the underlying mechanisms, we incubated mouse neuroblastoma 2A cells with 2,9-dimethyl-beta-carbolinium ion, and compared the findings with effects of norharman, the precursor beta-carboline of methylated derivatives, and with 1-methyl-4-phenyl-pyridinium. 2,9-Dimethyl-beta-carbolinium ion caused a significant increase of reactive oxygen species (higher efficiency than 1-methyl-4-phenyl-pyridinium) and of mitochondrial membrane potential within the first minutes. After 60 min, the membrane potential dissipated. Concomitantly, the levels of glutathione increased in 2,9-dimethyl-beta-carbolinium ion but not in 1-methyl-4-phenyl-pyridinium treated cells. After 24 h effector caspases 3 and 7 were activated and the number of apoptotic cells increased as revealed by fluorescence-activated cell sorting cytometry. When incubated longer (48 h), cells underwent late apoptosis/secondary necrosis as shown by fluorescence-activated cell sorting analysis and confirmed qualitatively by an electron microscopy study. The effects of 2,9-dimethyl-beta-carbolinium ion on apoptotic changes were similar to those induced by 1-methyl-4-phenyl-pyridinium(,) while norharman showed only a weak potency at the very high doses. To investigate whether 2,9-dimethyl-beta-carbolinium ion is neurotoxic under in vivo conditions and whether only dopaminergic neurones are affected we conducted a dose-response study. Three weeks after injection of 2,9-dimethyl-beta-carbolinium ion in the substantia nigra we found a dose-dependent decrease of dopamine and its metabolites in the striatum of rats. The levels of 5-hydroxytryptamine were diminished although the decrease was less. The levels of noradrenaline increased after some doses. The findings strongly suggest an important role of endogenous beta-carbolines in neurodegeneration with apoptosis as the predominant mechanism.
Asunto(s)
1-Metil-4-fenilpiridinio/toxicidad , Apoptosis/efectos de los fármacos , Carbolinas/toxicidad , Neurotoxinas/toxicidad , 1-Metil-4-fenilpiridinio/química , Animales , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo/métodos , Humanos , Ratones , Microscopía Electrónica/métodos , Neuroblastoma/ultraestructura , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Factores de TiempoRESUMEN
The aim of the present study was to find out whether (+/-)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical 5-HT1A agonist, and (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with serotonin 5-HT1A-agonist and dopamine D2-like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously measured the mechanical muscle resistance (MMG) of the rat's hind foot to passive movements in the ankle joint, and the EMG activity of two antagonist muscles. Both 8-OH-DPAT (0.125-0.5 mg/kg i.p.) and EMD 128130 (1-10 mg/kg i.p.) dose-dependently decreased the haloperidol-enhanced MMG to passive movements, as well as the tonic and the long-latency reflex EMG activities. Provided these results can be extrapolated to humans, the efficacy of EMD 128130 in relieving the haloperidol-induced muscle rigidity supports the concept that novel antipsychotics with 5-HT1A agonist and dopamine D2 antagonist activities should have a favourable extrapyramidal side-effect profile.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Antiparkinsonianos/farmacología , Haloperidol/toxicidad , Rigidez Muscular/inducido químicamente , Agonistas del Receptor de Serotonina 5-HT1 , Animales , Masculino , Rigidez Muscular/fisiopatología , Compuestos Orgánicos , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/fisiología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
The effect of acute administration of 1,2,3,4-tetrahydroisoquinoline, an endogenous substance suspected of producing Parkinsonism in humans, on the levels of glutathione and reactive oxygen species and on the enzymatic activity of gamma-glutamyl transpeptidase was investigated in the substantia nigra, striatum and cortex of rat brain. Four hours after a single dose of 1,2,3,4-tetrahydroisoquinoline (100 mg/kg i.p.), a significant increase in tissue glutathione level was found in the dopaminergic structures studied. The most pronounced effect was observed in the substantia nigra and cortex, and the weakest in the striatum. At the same time, significant inhibition of gamma-glutamyl transpeptidase was observed in the substantia nigra, cortex and striatum whose extent strictly corresponded to the increase in glutathione levels in those structures. Moreover, in 1,2,3,4-tetrahydroisoquinoline-treated rats, the production of reactive oxygen species was significantly reduced in the substantia nigra, whereas it was markedly enhanced in the striatum.Our results suggest that the increase in tissue glutathione level in the dopaminergic structures studied results from inhibition of gamma-glutamyl transpeptidase and refers to the extracellular pool of this peptide. Moreover, it is likely that both the 1,2,3,4-tetrahydroisoquinoline-induced alterations in glutathione level and the enhanced production of reactive oxygen species in the striatum may have implications for the pathogenesis of Parkinson's disease.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Glutatión/metabolismo , Isoquinolinas/administración & dosificación , Neurotoxinas/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Tetrahidroisoquinolinas , gamma-Glutamiltransferasa/metabolismo , Animales , Isoquinolinas/farmacología , Masculino , Neurotoxinas/farmacología , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The effect of single and multiple 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. In addition, the spontaneous and apomorphine-stimulated locomotor activity, and muscle rigidity was studied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated structures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affected. The level of DOPAC was strongly depressed (by 60-70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170-200%). In contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximately 60%) and increased the level of total metabolite, HVA, (by 40%) especially in the striatum, but the levels of DOPAC and 3MT remained unchanged. The paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopamine catabolism. Potential neuroprotective compound 1MeTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the monoamine oxidase (MAO)-dependent catabolic pathway and significantly activated the catechol-O-methyltransferase (COMT)-dependent O-methylation. In contrast 1BnTIQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO-dependent catabolic pathway. Interestingly, both compounds produced similar antidopaminergic functional effects: antagonism of apomorphine hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properties endogenous brain tetrahydroisoquinoline derivatives.
Asunto(s)
Dopamina/análogos & derivados , Dopamina/metabolismo , Isoquinolinas/farmacología , Tetrahidroisoquinolinas , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/metabolismo , Antagonistas de Dopamina/farmacología , Ácido Homovanílico/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Núcleo Accumbens/metabolismo , Ratas , Ratas Wistar , Sustancia Negra/metabolismoRESUMEN
The aim of the study was to assess the contribution of central dopaminergic and glutamatergic systems to the age-dependent loss of motor functions in rats. Rats of three age groups were compared: young (3-5-month-old), middle-aged (20-21-month-old) and old (29-31-month-old). The obtained results showed an age-dependent decline in the electromyographic (EMG) resting and reflex activities in the gastrocnemius and tibialis anterior muscles, as well as in the T-maze performance. Although these disturbances were accompanied with significant age-dependent decreases in the binding to NMDA, AMPA and dopamine D2 receptors, and a decline in the number of nigral dopamine neurons, they were significantly correlated with the loss of the binding to NMDA receptors only. The reduction in T-maze performance with aging was additionally correlated with a decrease in motor functions (EMG activity). The study suggests a crucial role of the loss of NMDA receptors in age-dependent motor disabilities, as well as in disturbances measured in the T-maze.
Asunto(s)
Envejecimiento/metabolismo , Dopamina/fisiología , Ácido Glutámico/fisiología , Trastornos del Movimiento/etiología , Proteínas del Tejido Nervioso/análisis , Receptores de N-Metil-D-Aspartato/análisis , Envejecimiento/psicología , Animales , Articulación del Tobillo/fisiopatología , Biomarcadores , Fenómenos Biomecánicos , Mapeo Encefálico , Recuento de Células , Maleato de Dizocilpina/metabolismo , Electromiografía , Femenino , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/metabolismo , Discapacidades para el Aprendizaje/patología , Aprendizaje por Laberinto , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Proteínas del Tejido Nervioso/fisiología , Docilidad , Desempeño Psicomotor , Racloprida/metabolismo , Ratas , Ratas Wistar , Tiempo de Reacción , Receptores AMPA/análisis , Receptores AMPA/metabolismo , Receptores de Dopamina D2/análisis , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/análisis , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
The aim of the present study was to find out whether blockade of adenosine A(2A) receptors by a selective antagonist, SCH 58261, influenced parkinsonian-like muscle rigidity. Muscle tone was examined using a combined mechano- and electromyographic method which simultaneously measured muscle resistance (MMG) of a rat hindfoot to passive extension and flexion in the ankle joint and electromyographic activity (EMG) of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity produced by reserpine (5 mg/kg + alpha-methyl-p-tyrosine, 250 mg/kg) was antagonized by SCH 58261 (0.1-5 mg/kg). SCH 58261 (5 mg/kg) also reduced reserpine-enhanced tonic and reflex EMG activities in both the gastrocnemius and the tibialis muscles. Moreover, SCH 58261 in doses of 1 and 5 mg/kg abolished muscle resistance induced by haloperidol (0.5 mg/kg). However, only the highest dose of SCH 58261 (5 mg/kg) decreased tonic EMG activity enhanced by haloperidol. Administration of L-DOPA (75 and 100 mg/kg) dose-dependently decreased the muscle resistance as well as tonic EMG activity evoked by haloperidol. Combined administration of SCH 58261 (0.1 mg/kg) and L-DOPA (50 mg/kg) in doses which did not affect the haloperidol-induced muscle rigidity produced a pronounced synergistic effect. The ability of SCH 58261 to diminish the parkinsonian-like muscle rigidity and to potentiate the effect of L-DOPA in this model seems to indicate a therapeutic value of this compound in the treatment of Parkinson's disease.
Asunto(s)
Rigidez Muscular/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/farmacología , Receptores Purinérgicos P1/metabolismo , Triazoles/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Animales , Articulación del Tobillo/efectos de los fármacos , Articulación del Tobillo/fisiología , Dopaminérgicos/farmacología , Antagonistas de Dopamina/farmacología , Combinación de Medicamentos , Electromiografía , Haloperidol/farmacología , Levodopa/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neostriado/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , Receptor de Adenosina A2A , Reserpina/farmacologíaRESUMEN
The aim of the present study was to determine whether S-4-carboxy-3-hydroxyphenylglycine (S)-4C3HPG, a mixed group I glutamate metabotropic receptor antagonist and a group II agonist, attenuated parkinsonian-like muscle rigidity in rats. Muscle tone was examined using a combined mechano and electromyographic method, which measured simultaneously the muscle resistance (MMG) of the rat's hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity was induced by pretreatment with haloperidol (1 mg/kg i.p.). (S)-4C3HPG injected in doses of 5 and 15 microg/0.5 microl bilaterally, into the rostral region of the striatum, decreased both the haloperidol-induced muscle rigidity (MMG) and the enhanced electromyographic activity (EMG). The present results suggest that blockade of mGluR1 receptors and/or activation of mGluR2 ones, localized in the rostral part of the striatum, may be responsible for the anti-parkinsonian effect of (S)-4C3HPG.
Asunto(s)
Cuerpo Estriado/fisiopatología , Glicina/farmacología , Rigidez Muscular/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Antidiscinéticos , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Electromiografía , Glicina/análogos & derivados , Haloperidol , Masculino , Microinyecciones , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , Tarso Animal/fisiologíaRESUMEN
It has been shown that the primary striatal dopaminergic hypofunction which is at the origin of Parkinson's disease, results in a secondary hyperactivity of glutamatergic neurotransmission. In the search for a therapy of Parkinson's disease, ionotropic, mainly NMDA, receptor antagonists were found to have moderately beneficial, yet also some undesirable side-effects. Therefore the present study was aimed at determining whether some metabotropic glutamate receptor (mGluR) ligands may have antiparkinsonian effects in the haloperidol-induced muscle rigidity. To this end three mGluR ligands were used: the potent and selective mGluR I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), the mixed group II agonist/ group I antagonist (S)-4-carboxy-3-hydroxyphenyl-glycine ((S)-4-C3HPG), and the potent group II agonist (+)-2-aminobicyclo[3.1.0.]hexane-2,6,-dicarboxylic acid (LY354740). Only LY354740 penetrated the brain from the periphery; for this reason other drugs were injected bilaterally into the rostral striatum or nucleus accumbens. The muscle tone was recorded by a mechanomyographic/electromyographic (MMG/EMG) method which measured the resistance of a rat's hind foot and the EMG reflex response of its muscles to passive movements. (S)-4C3HPG (5 and 15 microg/0.5 microl) and LY354740 (5 and 10mg/kg i.p.) diminished the muscle rigidity induced by haloperidol (1 mg/kg i.p.). AIDA (0.5-15 microg/0.5 microl) injected into the striatum was only slightly effective in the highest dose used. However, when injected into the nucleus accumbens AIDA (15microg/0.5microl) significantly and strongly counteracted the haloperidol-induced muscle rigidity. Our results suggest that stimulation of group II striatal mGluRs seems to play a major role in diminution of parkinsonian-like muscle rigidity. However, it seems that the antagonism of group I mGluRs located in the nucleus accumbens may also be of importance to the antiparkinsonian effect.
Asunto(s)
Glicina/análogos & derivados , Rigidez Muscular/fisiopatología , Enfermedad de Parkinson/fisiopatología , Receptores de Glutamato Metabotrópico/fisiología , Animales , Compuestos Bicíclicos con Puentes/farmacología , Electromiografía , Glicina/farmacología , Ligandos , Masculino , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
The effects of acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline, an endogenous substance suspected of producing parkinsonism in humans, on the muscle tone and metabolism of dopamine in the striatum, and on the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra were investigated in rats. Muscle tone was examined using a combined mechanomyographic and electromyographic method which measured simultaneously the muscle resistance of the rat's hind foot to passive extension and flexion in the ankle joint and electromyographic activity of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. 1,2,3,4-Tetrahydroisoquinoline administered at doses of 50 and 100 mg/kg intraperitoneally for 19 days increased muscle resistance 1 h after the first injection (acute treatment), 1 h after the last injection (chronic treatment) and three days after compound withdrawal. Rigidity observed on the third day of 1,2,3,4-tetrahydroisoquinoline withdrawal was accompanied by an increased tonic (resting) electromyographic activity of the gastrocnemius and tibialis anterior muscles. At the same time, a significant reduction in the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and a decrease in the dopamine level in the striatum were also found. A declining number of tyrosine hydroxylase-immunoreactive neurons in the whole substantia nigra showed a significant negative correlation with the enhanced muscle resistance, as well as with the tonic electromyographic activity recorded at rest, i.e. before the start of movements, from the gastrocnemius and tibialis anterior muscles. Our results suggest that 1,2,3,4-tetrahydroisoquinoline may be one of the endogenous substances involved in the progress of Parkinson's disease.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Isoquinolinas/farmacología , Tono Muscular/efectos de los fármacos , Sustancia Negra/enzimología , Tetrahidroisoquinolinas , Tirosina 3-Monooxigenasa/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Electromiografía , Inmunohistoquímica , Masculino , Microdiálisis , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Factores de TiempoRESUMEN
The aim of the present study was to assess the efficacy of pramipexole (2-amino-4,5,6, 7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride), a new dopamine D(2)/D(3) receptor agonist, to attenuate parkinsonian-like muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method, which simultaneously measured the muscle resistance of a rat's hindlimb to passive extension and flexion at the ankle joint, and the EMG acitivity of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity was produced by reserpine (5 mg/kg) injected in combination with alpha-methyl-p-tyrosine (250 mg/kg) or by haloperidol (0.5 mg/kg). Pramipexole in doses of 0.5-5 mg/kg antagonized both reserpine+alpha-methyl-p-tyrosine- and haloperidol-induced muscle rigidity. Pramipexole also reduced reserpine-enhanced tonic and reflex EMG activities in the gastrocnemius muscle. The present results suggest that stimulation of the postsynaptic dopamine receptor may be chiefly responsible for the antiparkinsonian action of pramipexole. The ability of pramipexole to diminish the parkinsonian-like muscle rigidity seems to indicate a therapeutic value of this compound in the treatment of Parkinson's disease.
Asunto(s)
Agonistas de Dopamina/farmacología , Rigidez Muscular/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Tiazoles/farmacología , Animales , Benzotiazoles , Relación Dosis-Respuesta a Droga , Electromiografía/efectos de los fármacos , Haloperidol/efectos adversos , Masculino , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/fisiopatología , Pramipexol , Ratas , Ratas Wistar , Reserpina/efectos adversos , Resultado del Tratamiento , alfa-Metiltirosina/efectos adversosRESUMEN
The aim of the present study was to assess contribution of striatal adenosine A2A receptors to regulation of the muscle tone in rats. The muscle tone was examined by a combined mechano- and electromyographic method, which measured simultaneously muscle resistance (MMG) of a rats hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles: gastrocnemius and tibialis anterior. CGS 21680 (1 and 2 microg/0.5 microl), injected bilaterally into the rostral part of the striatum, dose-dependently increased both MMG and the EMG. The present results show that stimulation of striatal adenosine A2A receptors by CGS 21680 evokes parkinsonian-like muscle rigidity which may be due to activation of the GABAergic strio-pallidal pathway.
Asunto(s)
Adenosina/análogos & derivados , Articulación del Tobillo/efectos de los fármacos , Rigidez Muscular/fisiopatología , Tono Muscular/efectos de los fármacos , Fenetilaminas/farmacología , Agonistas del Receptor Purinérgico P1 , Receptores Purinérgicos P1/efectos de los fármacos , Adenosina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Electromiografía , Masculino , Tono Muscular/fisiología , Ratas , Ratas Wistar , Receptor de Adenosina A2A , Receptores Purinérgicos P1/fisiologíaRESUMEN
The aim of the present study was to find out whether the classic neuroleptic fluphenazine is a good model compound for inducing parkinsonian-like muscle rigidity in rats. The muscle tone was measured as resistance developed by the rat's hind foot to passive flexion and extension. Fluphenazine in doses of 0.4-3.0 mg/kg i.p. induced a dose-dependent increase in the hind foot resistance to passive movements. The muscle rigidity induced by fluphenazine 1.5 mg/kg i.p.) was counteracted in a dose-dependent manner by the main antiparkinsonian drug L-DOPA (25-75 mg/kg i.p.). The present results suggest that the fluphenazine-induced muscle rigidity may be a useful model of parkinsonian rigidity.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Antipsicóticos , Antagonistas de Dopamina , Flufenazina , Levodopa/uso terapéutico , Rigidez Muscular/tratamiento farmacológico , Animales , Femenino , Rigidez Muscular/inducido químicamente , Ratas , Ratas WistarRESUMEN
The aim of the present study was to assess the contribution of the glycine site of NMDA receptors in the striatum to the regulation of muscle tone. Muscle tone was examined using a combined mechanoand electromyographic method, which measured simultaneously the muscle resistance (MMG) of the rat's hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity was induced by haloperidol (2.5 mg/kg i.p.). 5,7-dichlorokynurenic acid (5,7-DCKA), a selective glycine site antagonist, injected in doses of 2.5 and 4.5 microg/0.5 microl bilaterally, into the rostral region of the striatum, decreased both the haloperidol-induced muscle rigidity (MMG) and the enhanced electromyographic activity (EMG). 5,7-DCKA injected bilaterally in a dose of 4.5 microg/0.5 microl into the intermediate-caudal region of the striatum of rats not pretreated with haloperidol had no effect on the muscle tone. The present results suggest that blockade of the glycine site of NMDA receptors in the rostral part of the striatum may be mainly responsible for the antiparkinsonian action of this drug.
Asunto(s)
Cuerpo Estriado/fisiología , Glicina/metabolismo , Tono Muscular/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Sitios de Unión , Electromiografía/efectos de los fármacos , Masculino , Tono Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Ratas , Ratas WistarRESUMEN
The aim of the study was to examine the effect of antagonists of the NMDA receptor on the parkinsonian-like muscle rigidity in rats. Reserpine and haloperidol increased the muscle resistance of the hind foot to passive movements, as well as the reflex electromyographic (EMG) activity in the gastroenemius and tibialis anterior muscles. MK-801 (0.32-1.28 mg/kg s.c.), an uncompetitive antagonist of the NMDA receptor, and L-701,324 (5-40 mg/kg i.p.), an antagonist of the glycine site, reduced the muscle tone and the reflex EMG activity enhanced by reserpine or haloperidol. AP-5 (2 and 5 micrograms/0.5 microliter), a competitive antagonist of the NMDA receptor, and 5,7-dichlorokynurenic acid (1.0-4.5 micrograms/0.5 microliter), the glycine site antagonist injected bilaterally into the rostral striatum, inhibited the muscle rigidity induced by haloperidol. In contrast, AP-5, injected alone bilaterally into the intermediate-caudal striatum induced muscle rigidity. The present results suggest that: (1) the inhibitory effect of the NMDA receptor antagonists on the parkinsonian-like muscle rigidity depends, at least partly, on their action on the rostral striatum; (2) the blockade of NMDA receptors in the intermediate-caudal striatum may reduce the beneficial impact of these compounds.