RESUMEN
The aim of this study was to develop a quantitative scale to assess levodopa-induced dyskinesias (LIDs) in nonhuman primates using a video-based scoring system [Quantitative Dyskinesia Scale (QDS)]. Six macaques with stable Parkinsonism and LID were used for tests of the new QDS, in comparison with our current standardized scale (Drug-Related Side effects), which provides a classic subjective measurement of dyskinesia. QDS scoring is based on systematic movement counts in time frames, using videotape recordings. For both scales, body segments scored included each extremity, the trunk, the neck, and the face, and raters were blinded to L-dopa treatments. Comparison of the two scales revealed that their scores are highly correlated with and are parallel to the L-dopa pharmacokinetic profile, although the QDS provided significantly more quantifiable measurements. This remained the case after separating animals into groups of mild and severe dyskinesias. Inter-rater reliability for application of the QDS was confirmed from scores obtained by three examiners. We conclude that the QDS is a quantitative tool for reliably scoring LID in parkinsonian monkeys at all levels of severity of dyskinesia. The application of this new standard for scoring LID in primates will allow for more precise measurements of the effects of experimental treatments and will improve the quality of results obtained in translational studies.
Asunto(s)
Antiparkinsonianos/toxicidad , Discinesia Inducida por Medicamentos/clasificación , Levodopa/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Antiparkinsonianos/farmacología , Discinesia Inducida por Medicamentos/etiología , Femenino , Levodopa/farmacología , Macaca fascicularis , Macaca mulatta , Masculino , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Grabación en VideoRESUMEN
Smoking during pregnancy is associated with long lasting, hippocampus dependent, cognitive deficits in children. The current study was performed to investigate the effect of prenatal nicotine exposure on excitatory synaptic physiology and cellular signaling in the hippocampus using a rodent model. Excitatory synaptic physiology was analyzed using electrophysiological methods to detect changes in synaptic plasticity, excitatory synaptic transmission and synaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the hippocampus. Additionally, western blot experiments were performed to quantify alterations in protein expression levels in the hippocampus. Prenatal nicotine exposure resulted in a decrease in long term potentiation (LTP) and an increase in long term depression (LTD). Basal synaptic transmission was also reduced with a concomitant decline in AMPAR mediated synaptic currents at the cellular and single channel levels. Presynaptic pool of vesicles docked close to release sites were also diminished in nicotine exposed rats. Moreover, reduced levels of ß2 subunit containing nicotinic receptors and extracellular signal regulated kinase1/2 (ERK1/2) were observed in nicotine exposed rats. These results suggest that long lasting alterations in excitatory synaptic physiology, AMPAR synaptic currents and ERK1/2 signaling may serve as the molecular mechanisms for cognitive deficits associated with prenatal nicotine exposure.
Asunto(s)
Hipocampo/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nicotina/farmacología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptores Nicotínicos/metabolismo , Sinapsis/efectos de los fármacos , Animales , Femenino , Hipocampo/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Plasticidad Neuronal/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus.
Asunto(s)
Potenciación a Largo Plazo/efectos de los fármacos , Memoria/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Animales , Potenciales Postsinápticos Excitadores , Hipocampo/citología , Hipocampo/fisiología , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Purinas/farmacología , Citrato de SildenafilRESUMEN
Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.
Asunto(s)
Amantadina/uso terapéutico , Metanfetamina/envenenamiento , Síndromes de Neurotoxicidad/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Dopamina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Mitocondriales/inducido químicamente , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Serotonina/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
In the developing brain, nicotinic acetylcholine receptors (nAChRs) are involved in cell survival, targeting, formation of neural and sensory circuits, and development and maturation of other neurotransmitter systems. This regulatory role is disrupted when the developing brain is exposed to nicotine, which occurs with tobacco use during pregnancy. Prenatal nicotine exposure has been shown to be a strong risk factor for memory deficits and other behavioral aberrations in the offspring. The molecular mechanisms underlying these neurobehavioral outcomes are not clearly elucidated. We used a rodent model to assess behavioral, neurophysiological, and neurochemical consequences of prenatal nicotine exposure in rat offspring with specific emphasis on the hippocampal glutamatergic system. Pregnant dams were infused with nicotine (6 mg/kg/day) subcutaneously from the third day of pregnancy until birth. Results indicate that prenatal nicotine exposure leads to increased anxiety and depressive-like effects and impaired spatial memory. Synaptic plasticity in the form of long-term potentiation (LTP), basal synaptic transmission, and AMPA receptor-mediated synaptic currents were reduced. The deficit in synaptic plasticity was paralleled by declines in protein levels of vesicular glutamate transporter 1 (VGLUT1), synaptophysin, AMPA receptor subunit GluR1, phospho(Ser845) GluR1, and postsynaptic density 95 (PSD-95). These results suggest that prenatal nicotine exposure by maternal smoking could result in alterations in the glutamatergic system in the hippocampus contributing to the abnormal neurobehavioral outcomes.
Asunto(s)
Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Nicotina/toxicidad , Receptores de Glutamato/metabolismo , Animales , Electrofisiología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/biosíntesisRESUMEN
Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor DeltaFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of DeltaFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of DeltaFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic DeltaFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of DeltaFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high DeltaFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal DeltaFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.
Asunto(s)
Cuerpo Estriado/metabolismo , Discinesias/etiología , Discinesias/metabolismo , Levodopa/efectos adversos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Discinesias/clasificación , Lateralidad Funcional , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Mutación/fisiología , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-jun , Ratas , Ratas Sprague-Dawley , Estadísticas no Paramétricas , Simpaticolíticos/toxicidad , Factores de TiempoRESUMEN
In Parkinson's disease, depletion of dopamine in the striatum leads to various symptoms such as tremor, rigidity and akinesia. Methamphetamine use has significantly increased in USA and around the world and there are several reports showing that its long-term use increases the risk for dopamine depletion. However, the toxic mechanisms of methamphetamine are not well understood. This study was undertaken to gain greater mechanistic understanding of the toxicity induced by methamphetamine. We evaluated the effect of methamphetamine on the generation of reactive oxygen species, mitochondrial monoamine oxidase, complex I & IV activities. Behavioral analysis evaluated the effect on catalepsy, akinesia and swim score. Neurotransmitter levels were evaluated using high pressure liquid chromatography (HPLC) electrochemical detection (ECD). Results showed that methamphetamine caused significant generation of reactive oxygen species and decreased complex I activity in the mitochondria leading to dopamine depletion in the striatum.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Metanfetamina/toxicidad , Sustancia Negra/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiología , Electroquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sustancia Negra/enzimología , Sustancia Negra/metabolismo , Sustancia Negra/fisiologíaRESUMEN
Sickle cell disease is a hemoglobinopathy that causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. The development and treatment of pain, in particular, neuropathic pain in sickle cell disease patients is poorly understood and impedes our progress toward the development of novel therapies to treat pain associated with sickle cell disease. The orexin/hypocretin system offers a novel approach to treat chronic pain and hyperalgesia. These neuropeptides are synthesized in three regions: perifornical area (PFA), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH). Data suggest that orexin-A neuropeptide has an analgesic effect on inflammatory pain and may affect mechanisms underlying the maintenance of neuropathic pain. The purpose of this study was to determine whether there are neuronal activation differences in the orexin system as a result of neuropathic pain testing in a mouse model of sickle cell disease. Female transgenic sickle mice that express exclusively (99%) human sickle hemoglobin (HbSS-BERK) and age-/gender-matched controls (HbAA-BERK mice; n = 10/group, 20-30 g) expressing normal human hemoglobin A were habituated to each test protocol and environment before collecting baseline measurements and testing. Four measures were used to assess pain-related behaviors: thermal/heat hyperalgesia, cold hyperalgesia, mechanical hyperalgesia, and deep-tissue hyperalgesia. Hypothalamic brain sections from HbAA-BERK and HbSS-BERK mice were processed to visualize orexin and c-Fos immunoreactivity and quantified. The percentage of double labeled neurons in the PFA was significantly higher than the percentage of double labeled neurons in the LH orexin field of HbAA-BERK mice (* p < 0.05). The percentages of double labeled neurons in PFA and DMH orexin fields are significantly higher than those neurons in the LH of HbSS-BERK mice (* p < 0.05). These data suggest that DMH orexin neurons were preferentially recruited during neuropathic pain testing and a more diverse distribution of orexin neurons may be required to produce analgesia in response to pain in the HbSS-BERK mice. Identifying specific orexin neuronal populations that are integral in neuropathic pain processing will allow us to elucidate mechanisms that provide a more selective, targeted approach in treating of neuropathic pain in sickle cell disease.
RESUMEN
Coenzyme Q10, an endogenous lipophilic antioxidant, plays an indispensable role in ATP synthesis. The therapeutic value of coenzyme Q10 in Parkinson's disease and other neurodegenerative disorders is still being tested and the preliminary results are promising. The 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP)-treated mouse is a valid and accepted animal model for Parkinson's disease. 1-methyl-4-phenylpyridinium (MPP(+)) is an active toxic metabolite of MPTP. MPP(+) and MPTP are known to induce oxidative stress and mitochondrial dysfunction. However, the effect of MPP(+) and MPTP on coenzyme Q is not clearly understood. The present study investigated the in vitro and in vivo effect of MPP(+) and MPTP on coenzyme Q content. Coenzyme Q content was measured using HPLC-UV detection methods. In the in vitro studies, MPP(+) (0-50 microM) was incubated with SH-SY5Y human neuroblastoma cells and NG-108-15 (mouse/rat, neuroblastomaxglioma hybrid) cells. MPP(+) concentration dependently increased coenzyme Q10 content in SH-SY5Y cells. In NG-108-15 cells, MPP(+) concentration dependently increased both coenzyme Q9 and Q10 content. In the in vivo study, mice were administered with MPTP (30 mg/kg, twice 16 h apart) and sacrificed one week after the last administration. Administration of MPTP to mice significantly increased coenzyme Q9 and coenzyme Q10 levels in the nigrostriatal tract. However, MPTP did not affect the coenzyme Q content in the cerebellum, cortex and pons. This study demonstrated that MPP(+)/MPTP significantly affected the coenzyme Q content in the SH-SY5Y and NG-108 cells and in the mouse nigrostriatal tract.
Asunto(s)
1-Metil-4-fenilpiridinio/toxicidad , Dopaminérgicos/toxicidad , Intoxicación por MPTP , Ubiquinona/metabolismo , Animales , Línea Celular Tumoral , Cerebelo/efectos de los fármacos , Cerebelo/enzimología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/enzimología , Cromatografía Líquida de Alta Presión , Humanos , Intoxicación por MPTP/enzimología , Intoxicación por MPTP/etiología , Ratones , Ratones Endogámicos C57BL , Puente/efectos de los fármacos , Puente/enzimología , Ubiquinona/análisisRESUMEN
Sildenafil, a phosphodiesterase-5 inhibitor is widely used for the treatment of erectile dysfunction. Recently, the FDA approved the use of sildenafil in the therapeutic treatment of pulmonary arterial hypertension. Sildenafil crosses the blood-brain barrier and has been shown to enhance memory. Tremor, rigidity and akinesia are the most common symptoms seen in Parkinson's disease. Fatigue and sexual dysfunction are the other prominent features seen in Parkinson's disease. Interestingly, sildenafil is used therapeutically to treat sexual dysfunction in Parkinson's disease patients. Currently research on Parkinson's disease focuses on developing novel drug therapies for retarding the nigral dopaminergic neurodegeneration. Hence, we investigated the anti-fatigue and neuroprotective effects of sildenafil. In this study, the effect of sildenafil on fatigue was evaluated using forced swim test in mice. Sildenafil had no effect on fatigue as seen by the swim time. With regard to neuroprotective effects, we investigated the effects of sildenafil using two animal models of Parkinson's disease. In this study, 6-hydroxydopamine-lesioned (unilateral) rats and MPTP-treated mice were used as the animal models of Parkinson's disease. 6-Hydroxydopamine-lesioned rats were used to determine the effect of sildenafil on rotational behavior. Ipsilateral or contralateral rotational behavior can indicate the amphetamine-like activity or apomorphine-like activity of sildenafil. Sildenafil did not induce contralateral or ipsilateral rotations in 6-hydroxydopamine-lesioned rats. Sildenafil did not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in the striatum.
Asunto(s)
Fatiga/prevención & control , Fármacos Neuroprotectores/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Animales , Intoxicación por MPTP/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidopamina/toxicidad , Purinas/farmacología , Citrato de SildenafilRESUMEN
Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and is predominantly used in the treatment of erectile dysfunction. While maintaining an excellent safety and tolerability profile in the management of erectile dysfunction, sildenafil also provides a prolonged benefit in various other diseases. Sildenafil has been shown to have a potential therapeutic efficacy for disorders related to the central nervous system and pulmonary system. In the central nervous system, it exerts its neuroprotective effects in multiple sclerosis and has a significant memory enhancing action. Sildenafil also significantly enhances neurogenesis. Several lines of evidence indicate that targeting PDE5 with sildenafil offers novel strategies in the treatment of age-related memory impairment. Guanylate cyclase/cGMP/protein kinase G pathway or glutamate/nitric oxide/cGMP pathway appears to mediate memory enhancing effects. Some of the positive cognitive features of sildenafil therapy are likely attributable to the mechanisms reviewed here. Sildenafil has been shown to reduce pulmonary hypertension and alleviate pain in animals and humans. The present review primarily focuses on the various pharmacological effects of sildenafil with regard to its influence on the nervous and pulmonary system.
Asunto(s)
Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Sulfonas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Eréctil/tratamiento farmacológico , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/fisiología , Dolor/tratamiento farmacológico , Piperazinas/efectos adversos , Purinas/efectos adversos , Purinas/uso terapéutico , Citrato de Sildenafil , Sulfonas/efectos adversosRESUMEN
We evaluated the effect of ebselen on human SH-SY5Y dopaminergic neuronal cells and determined whether ebselen, a glutathione peroxidase-mimetic, protected against MPTP-induced dopamine depletion in mice. Ebselen (10-100 microM) inhibited the proliferation of SH-SY5Y cells dose-dependently. Ebselen did not induce any behavioral changes and did not block MPTP-induced tremor and akinesia. Ebselen had no effect on the monoamine oxidase activity and did not protect against MPTP-induced dopamine depletion in striatum.
Asunto(s)
Azoles/farmacología , Encéfalo/efectos de los fármacos , Dopamina/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Compuestos de Organoselenio/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/antagonistas & inhibidores , Animales , Antioxidantes/farmacología , Azoles/uso terapéutico , Encéfalo/metabolismo , Encéfalo/fisiopatología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glutatión Peroxidasa/metabolismo , Humanos , Isoindoles , Ratones , Ratones Endogámicos C57BL , Monoaminooxidasa/efectos de los fármacos , Monoaminooxidasa/metabolismo , Neuronas/metabolismo , Compuestos de Organoselenio/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Resultado del Tratamiento , Temblor/tratamiento farmacológico , Temblor/metabolismo , Temblor/fisiopatologíaRESUMEN
Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson's disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6-8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.
Asunto(s)
Discinesia Inducida por Medicamentos/cirugía , Fibroblastos/trasplante , Trastornos Parkinsonianos/cirugía , Animales , Antiparkinsonianos/efectos adversos , Globo Pálido/cirugía , Levodopa/efectos adversos , Macaca mulattaRESUMEN
Phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium spiny neurons of both the direct and indirect output pathways. Similar to dopamine D2 receptor antagonists acting on indirect pathway neurons, PDE10A inhibitors have shown behavioral effects in rodent models that predict antipsychotic efficacy. These findings have supported the clinical investigation of PDE10A inhibitors as a new treatment for schizophrenia. However, PDE10A inhibitors and D2 antagonists differ in effects on direct pathway and other neurons of the basal ganglia, indicating that these two drug classes may have divergent antipsychotic efficacy and side effect profile. In the present study, we compare the behavioral effects of the selective PDE10A inhibitor MP-10 to those of the clinical standard D2 antagonist risperidone in rhesus monkeys using a standardized motor disability scale for parkinsonian primates and a newly designed "Drug Effects on Nervous System" scale to assess non-motor effects. Behavioral effects of MP-10 correlated with its plasma levels and its regulation of metabolic activity in striatal and cortical regions as measured by FDG-PET imaging. While MP-10 and risperidone broadly impacted similar behavioral domains in the primate, their effects had a different underlying basis. MP-10-treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions. These findings are discussed in light of what is currently known about the modulation of striatal circuitry by these two classes of compounds, and provide insight into interpreting emerging clinical data with PDE10A inhibitors for the treatment of psychotic symptoms.
Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Pirazoles/farmacología , Quinolinas/farmacología , Risperidona/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Macaca mulatta , Masculino , Inhibidores de Fosfodiesterasa/sangre , Pirazoles/sangre , Quinolinas/sangre , Esquizofrenia/tratamiento farmacológicoRESUMEN
Research into therapeutics for neuropsychiatric disorders is increasingly focusing on drugs with new mechanisms of action, and such agents are often assessed in preclinical studies using nonhuman primates. However, researchers lack a standardised method to compare different drugs for common adverse effects on the nervous system. We have developed a new scale for this purpose, named "Drug Effects on the Nervous System" (DENS), and tested its utility in an analysis of the second-generation antipsychotic risperidone in monkeys. The behavioural effects of risperidone over a ten-fold clinically relevant exposure range were rated with the DENS scale and compared with a standard motor disability scale for primates. The ratings were correlated with projected D2 and 5-HT2A receptor occupancies over time. The DENS scale detected dose-dependent side effects of risperidone in addition to the motor effects detected with the motor disability scale, including cognitive, sensorimotor and autonomic functions. A consistent temporal association between the DENS scale changes and the projected D2 receptor occupancy was observed, and the DENS scale ratings demonstrated high inter-rater reliability. These results demonstrate the usefulness of the DENS scale as a highly sensitive, reliable and accurate method to identify common adverse effects of risperidone and potentially other neurotropics for translational studies in primates.
Asunto(s)
Sistema Nervioso/efectos de los fármacos , Psicotrópicos/efectos adversos , Algoritmos , Animales , Antipsicóticos/efectos adversos , Antipsicóticos/metabolismo , Antipsicóticos/farmacocinética , Sistema Nervioso Autónomo/efectos de los fármacos , Enfermedades de los Ganglios Basales/fisiopatología , Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Discinesia Inducida por Medicamentos/fisiopatología , Femenino , Macaca fascicularis , Macaca mulatta , Masculino , Variaciones Dependientes del Observador , Psicotrópicos/metabolismo , Psicotrópicos/farmacocinética , Receptores de Droga/metabolismo , Estándares de Referencia , Risperidona/efectos adversos , Risperidona/metabolismo , Risperidona/farmacocinéticaRESUMEN
Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD) and other forms of parkinsonism. The anatomical or pathophysiological correlates are poorly understood largely due to the lack of a well-established animal model. Here we studied whether FOG is reproduced in the non-human primate (NHP) model of PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (Genus Macaca, n=29) were examined for the development of FOG, and the leg movements were recorded with accelerometry. The relationships between developing FOG and the animals' characteristics, the MPTP treatments, and the modeled outcomes were determined. In parkinsonian monkeys FOG developed frequently (48%) manifesting similar characteristics to those seen in PD patients. In addition, FOG episodes in the monkey were accompanied by leg trembling with the typical duration (2-10s) and frequency (~7 Hz). The development of NHP FOG was significantly associated with the severity of parkinsonism, as shown by high motor disability scores (≥ 20) and levodopa-induced dyskinesia scores (p=0.01 and p=0.04, respectively). Differences in demographics and MPTP treatments (doses, treatment duration, etc.) had no influence on NHP FOG occurrence, with the exception of gender that showed FOG predominance in males (p=0.03). The unique features of FOG in PD can be replicated in severely parkinsonian macaques, and this represents the first description of a FOG animal model.
Asunto(s)
Modelos Animales de Enfermedad , Trastornos Neurológicos de la Marcha/etiología , Cojera Animal/etiología , Trastornos Parkinsonianos/complicaciones , Animales , Femenino , Trastornos Neurológicos de la Marcha/fisiopatología , Cojera Animal/fisiopatología , Macaca , Masculino , Trastornos Parkinsonianos/fisiopatologíaRESUMEN
Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Región CA1 Hipocampal/metabolismo , Neuronas Colinérgicas/metabolismo , Potenciación a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Tabique del Cerebro/metabolismo , Sinaptosomas/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , Animales , Región CA1 Hipocampal/efectos de los fármacos , Colinérgicos/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Potenciales Evocados/efectos de los fármacos , Femenino , Técnicas para Inmunoenzimas , Potenciación a Largo Plazo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Saporinas , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/lesiones , Transmisión Sináptica/efectos de los fármacos , Sinaptosomas/efectos de los fármacosRESUMEN
In the present study, we investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on lipoamide dehydrogenase activity and metallothionein content. Lipoamide dehydrogenase is a flavoprotein enzyme, which reduces lipoamide and low molecular weight thiols. This enzyme has also been involved in the conversion of ubiquinone (coenzyme Q-10, oxidized form) to ubiquinol (reduced form). Lipoamide dehydrogenase activity was measured spectrophotometrically following its incubation with different doses of MPTP, MPP+, and divalent metals. MPTP at higher concentrations inhibited the lipoamide dehydrogenase activity, whereas it's potent toxic metabolite 1-methyl-4-phenylpyridinium (MPP+) had a similar effect at lower concentration. Calcium and copper did not affect the enzyme activity at any of the doses tested, whereas, zinc dose dependently enhanced the lipoamide dehydrogenase activity. Additionally, levels of metallothionein in the mouse nigrostriatal system were measured by cadmium affinity method following administration of MPTP. Metallothionein content was significantly reduced in the substantia nigra (SN), and not in the nucleus caudatus putamen (NCP) following a single administration of MPTP (30 mg/kg, i.p.). Our results suggests that both lipoamide dehydrogenase activity and metallothionein levels may be critical for dopaminergic neuronal survival in Parkinson's disease and provides further insights into the neurotoxic mechanisms involved in MPTP-induced neurotoxicity.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Dihidrolipoamida Deshidrogenasa/metabolismo , Metalotioneína/metabolismo , Neuronas/efectos de los fármacos , Neurotoxinas/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , 1-Metil-4-fenilpiridinio/metabolismo , 1-Metil-4-fenilpiridinio/farmacología , Animales , Calcio/metabolismo , Cobre/metabolismo , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos C57BL , Zinc/metabolismoRESUMEN
Parkinson's disease is a progressive neurological disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. It is the most common of the neurodegenerative movement disorders, affecting approximately 1% of the population over age 65. Though the exact cause of the neurodegeneration is unknown, it has been shown that environmental factors can contribute to the onset of Parkinson's disease. Parkinsonian symptoms are seen following exposure to the herbicide paraquat, and the fungicide maneb. Furthermore, evidence clearly shows that neurodegeneration develops in environments where workers are co-exposed to paraquat and maneb. These neurotoxins cause a pesticide-induced loss of dopaminergic neurons, inducing a Parkinsonian phenotype. The specific mechanisms by which these environmental neurotoxins affect the nigral dopaminergic neurons are unknown. This gap in mechanistic understanding raises a need for further examination of their cytotoxic effects. Despite advances in pharmacotherapy that have improved quality of life, the mortality rate among Parkinson's disease sufferers remains largely unchanged. There is need for a proactive treatment strategy that could provide neuroprotection or neurorestoration. Since evidence has shown that environmental neurotoxins play an important role in nigral degeneration, there is obviously a need to take a closer look at such toxins since a greater understanding could aid in development of novel pharmacological agents with anti-parkinson and neuroprotective effects. In this review, we intend to examine the role of environmental toxins, namely paraquat and maneb, in the neurotoxicity that leads to dopamine depletion.