RESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder that causes progressive dysfunction of dopaminergic and non-dopaminergic neurons, generating motor and nonmotor signs and symptoms. Pain is reported as the most bothersome nonmotor symptom in PD; however, pain remains overlooked and poorly understood. In this study, we evaluated the nociceptive behavior and the descending analgesia circuitry in a rat model of PD. Three independent experiments were performed to investigate: i) thermal nociceptive behavior; ii) mechanical nociceptive behavior and dopaminergic repositioning; and iii) modulation of the pain control circuitry. The rat model of PD, induced by unilateral striatal 6-hydroxydopamine (6-OHDA), did not interfere with thermal nociceptive responses; however, the mechanical nociceptive threshold was decreased bilaterally compared to that of naive or striatal saline-injected rats. This response was reversed by apomorphine or levodopa treatment. Striatal 6-OHDA induced motor impairments and reduced dopaminergic neuron immunolabeling as well as the pattern of neuronal activation (c-Fos) in the substantia nigra ipsilateral (IPL) to the lesion. In the midbrain periaqueductal gray (PAG), 6-OHDA-induced lesion increased IPL and decreased contralateral PAG GABAergic labeling compared to control. In the dorsal horn of the spinal cord, lesioned rats showed bilateral inhibition of enkephalin and µ-opioid receptor labeling. Taken together, we demonstrated that the unilateral 6-OHDA-induced PD model induces bilateral mechanical hypernociception, which is reversed by dopamine restoration, changes in the PAG circuitry, and inhibition of spinal opioidergic regulation, probably due to impaired descending analgesic control. A better understanding of pain mechanisms in PD patients is critical for developing better therapeutic strategies to improve their quality of life.
Asunto(s)
Cuerpo Estriado/fisiopatología , Nocicepción , Dolor/etiología , Trastornos Parkinsonianos/complicaciones , Sustancia Negra/fisiopatología , Animales , Apomorfina/farmacología , Conducta Animal , Agonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Calor , Hidroxidopaminas , Masculino , Red Nerviosa/efectos de los fármacos , Dolor/psicología , Umbral del Dolor , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Estimulación Física , Ratas , Ratas WistarRESUMEN
Parkinson's disease (PD) is described as a neurological condition, resulting from continuous degeneration of dopaminergic neurons. Currently, most treatments for neurodegenerative diseases are palliative. In traditional Iranian medicine, Citrus aurantium flower extract is used to treat some neural diseases, such as sleep disorders and anxiety. The tendency towards the use of medicinal herbs for the treatment of diseases (eg, seizure) is growing. Accordingly, we evaluated the antioxidant effects of C. aurantium flowers and analyzed their protective effects against 6-hydroxydopamine (6-OHDA)-mediated oxidative stress. In this study, 150 mM of 6-OHDA was used to induce cellular damage. Also, MTT assay was performed to analyze cellular viability. Fluorescence spectrophotometry was performed to measure the intracellular reactive oxygen species (ROS) and calcium levels. Based on the findings, 6-OHDA could reduce cell viability. We also analyzed the effects of C. aurantium against neurotoxicity. The intracellular levels of ROS and calcium greatly improved in cells exposed to 6-OHDA. SH-SY5Y cell incubation with C. aurantium (400 and 600 mg/mL) induced protective effects and decreased the biochemical markers of cell apoptosis. According to the findings, C. aurantium showed protective effects against neurotoxicity, caused by 6-OHDA; these protective properties were accompanied by antiapoptotic features. According to the findings, it seems that hydromethanolic C. aurantium extract can be used to prevent seizures.
La enfermedad de Parkinson (EP) se describe como una afección neurológica que resulta de la degeneración continua de las neuronas dopaminérgicas. Actualmente, la mayoría de los tratamientos para las enfermedades neurodegenerativas son paliativos. En la medicina tradicional iraní, el extracto de flor de Citrus aurantium se usa para tratar algunas enfermedades neurológicas, como los trastornos del sueño y la ansiedad. La tendencia hacia el uso de las medicinas para el tratamiento de enfermedades (por ejemplo, convulsiones) está creciendo. Por consiguiente, el objetivo de este trabajo consistió en evaluar los efectos antioxidantes de las flores de C. aurantium y analizar sus efectos protectores contra el estrés oxidativo mediado por la 6- hidroxidopamina (6-OHDA). En este estudio, se usó 150 mM de 6-OHDA para inducir daño celular. Además, se realizó un ensayo de MTT para analizar la viabilidad celular. La espectrofotometría de fluorescencia se realizó para medir las especies reactivas de oxígeno (ROS) intracelulares y los niveles de calcio. En base a los hallazgos, 6-OHDA podría reducir la viabilidad celular. También analizamos los efectos de C. aurantium contra la neurotoxicidad. Los niveles intracelulares de ROS y calcio se expandieron a las células expuestas a 6-OHDA. La incubación de células SH-SY5Y con C. aurantium (400 y 600 mg / ml) indujo efectos protectores y disminuyó los marcadores bioquímicos de la apoptosis celular. De acuerdo con los hallazgos, C. aurantium mostró efectos protectores contra la neurotoxicidad, causada por 6-OHDA; estas propiedades protectoras fueron acompañadas por características antiapoptóticas. Según los hallazgos, parece que el extracto hidrometanólico de C. aurantium se puede usar para prevenir las convulsiones.
Asunto(s)
Humanos , Enfermedad de Parkinson , Extractos Vegetales/farmacología , Citrus/química , Antioxidantes/farmacología , Espectrometría de Fluorescencia , Supervivencia Celular/efectos de los fármacos , Western Blotting , Especies Reactivas de Oxígeno , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Hidroxidopaminas/toxicidad , NeuroblastomaRESUMEN
OBJECTIVE: Parkinson's disease (PD) may be caused by the interaction of a number of factors, including genetics, toxins, oxidative stress, mitochondrial abnormalities, and aging. Studies have shown that consumption of an antioxidant-rich diet may reduce the incidence of neurodegenerative diseases. The aim of this study was to evaluate the role of the flavonoid hesperidin in an animal model of PD induced by 6-hidroxidopamine (6-OHDA). METHODS: Aged mice were treated with hesperidin (50 mg/kg) during 28 d after an intracerebroventricular injection of 6-OHDA. The enzymatic activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, the levels of glutathione, reactive oxygen species, total reactive antioxidant potential, dopamine and its levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, was analyzed in the striatum. The behavioral parameters (depressive-like, memory, and locomotor) were measured. RESULTS: This study demonstrated that hesperidin (50 mg/kg) treatment was effective in preventing memory impairment in the Morris water maze test, as well as, depressive-like behavior in the tail suspension test. Hesperidin attenuated the 6-OHDA-induced reduction in glutathione peroxidase and catalase activity, total reactive antioxidant potential and the dopamine and its metabolite levels in the striatum of aged mice. 6-OHDA increased reactive oxygen species levels and glutathione reductase activity in the striatum, and these alterations were mitigated by chronic administration of hesperidin. CONCLUSION: This study demonstrated a protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD.
Asunto(s)
Antioxidantes/uso terapéutico , Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Hesperidina/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Encéfalo/metabolismo , Depresión/etiología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Femenino , Hesperidina/farmacología , Suspensión Trasera , Hidroxidopaminas , Peroxidación de Lípido/efectos de los fármacos , Aprendizaje por Laberinto , Memoria/efectos de los fármacos , Trastornos de la Memoria/etiología , Ratones Endogámicos C57BL , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Parkinson's disease (PD) is characterized by progressive dopamine (DA) depletion in the striatum. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegeneration diseases. This study was designed to investigate the potential neuroprotective effect of swimming training (ST) in a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a 4-week ST was effective in attenuating the following impairments resulting from 6-OHDA exposure: (i) depressive-like behavior in the tail suspension test; (ii) increase in the number of falls in the rotarod test; (iii) impairment on long-term memory in the object recognition test; (iv) increase of the reactive species and interleukin 1-beta (IL-1ß) levels; (v) inhibition of the glutathione peroxidase (GPx) activity; (vi) rise of the glutathione reductase (GR) and glutathione S-transferase (GST) activities and vii) decrease of DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The mechanisms involved in this study are the modulation of GPx, GR and GST activities as well as IL-1ß level in a PD model induced by 6-OHDA, protecting against the decrease of DA, DOPAC and HVA levels in the striatum of mice. These findings reinforce that one of the effects induced by exercise on neurodegenerative disease, such as PD, is due to antioxidant and anti-inflammatory properties. We suggest that exercise attenuates cognitive and motor declines, depression, oxidative stress, and neuroinflammation induced by 6-OHDA supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of PD.
Asunto(s)
Terapia por Ejercicio/métodos , Hidroxidopaminas/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/rehabilitación , Natación/fisiología , Animales , Catalasa/metabolismo , Citrato (si)-Sintasa/metabolismo , Cuerpo Estriado/enzimología , Depresión/etiología , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/enzimología , Enfermedad de Parkinson/fisiopatología , Desempeño Psicomotor , Reconocimiento en Psicología , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
6-Hydroxydamine has widely been used as neurotoxin in preclinical studies related on the neurodegenerative process of dopaminergic neurons in Parkinson's disease based on its ability to be neurotoxic as a consequence of free radical formation during its auto-oxidation to topaminequinone. We report that 50-µM 6-hydroxydopamine is not neurotoxic in RCSN-3 cells derived from substantia nigra incubated during 24 h contrasting with a significant sixfold increase in cell death (16 ± 2 %; P < 0.001) was observed in RCSN-3NQ7 cells expressing a siRNA against DT-diaphorase that silence the enzyme expression. To observe a significant cell death in RCSN-3 cells induced by 6-hydroxydopamine (24 ± 1 %; P < 0.01), we have to increase the concentration to 250 µm while a 45 ± 2 % cell death (P < 0.001) was observed at this concentration in RCSN-3NQ7 cells. The cell death induced by 6-hydroxydopamine in RCSN-3NQ7 cells was accompanied with a (i) significant increase in oxygen consumption (P < 0.01), (ii) depletion of reduced glutathione and (iii) a significant decrease in ATP level (P < 0.05) in comparison with RCSN-3 cells. In conclusion, our results suggest that one-electron reduction of 6-hydroxydopamine quinone seems to be the main reaction responsible for 6-hydroxydopamine neurotoxic effects in dopaminergic neurons and DT-diaphorase seems to play an important neuroprotective role by preventing one-electron reduction of topaminequinone.
Asunto(s)
Electrones , Hidroxidopaminas/química , Hidroxidopaminas/toxicidad , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , Oxidopamina/química , Oxidopamina/toxicidad , Quinonas/química , Quinonas/toxicidad , Adenosina Trifosfato/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Oxidación-Reducción , Consumo de Oxígeno/efectos de los fármacos , Ratas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
The effects of chronic oral treatment with low doses of caffeine (1-3 mg/kg) and trihexyphenidyl (0.1-0.2 mg/kg) were tested on hemiparkinsonian rats, which received the following treatments in a counterbalanced order: vehicle, caffeine, trihexyphenidyl, and caffeine plus trihexyphenidyl. Three preclinical models were used: the stepping test, the cylinder test, and the staircase test. Compared to pre-lesion values, the forepaw contralateral to the dopamine-denervated side showed impaired stepping, fewer wall contacts in the cylinder test, and fewer pellets retrieved in the staircase test. In the stepping test both doses of caffeine produced a complete recovery of motor function (100%), whereas the effect of trihexyphenidyl was less intense (77-80%). In this same test the maximal effect of drugs did not develop tolerance during 2-3 weeks, and was completely reversible after drug cessation. In the cylinder test only the wall contacts performed simultaneously with both forepaws were significantly increased by caffeine (3 mg/kg) and trihexyphenidyl (0.2 mg/kg), and this effect was also reversible. In the staircase test none of the treatments improved food pellet retrieval with the contralateral forepaw. Altogether, these results show that chronic treatment with caffeine, at doses similar to daily human consumption, produces a sustained improvement in the use of the contralateral forelimb in unilaterally 6-hydroxydopamine denervated rats, without the development of tolerance. Although the combined administration of caffeine plus trihexyphenidyl showed no synergism in these models, the results suggest that low doses of caffeine (1-3 mg/kg/day) could be of therapeutic value for the reversal of motor symptoms in parkinsonian patients.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Cafeína/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/fisiopatología , Trihexifenidilo/uso terapéutico , Animales , Antiparkinsonianos/administración & dosificación , Encéfalo/patología , Cafeína/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/fisiología , Miembro Anterior/fisiología , Lateralidad Funcional/fisiología , Fuerza de la Mano/fisiología , Hidroxidopaminas , Inmunohistoquímica , Locomoción/fisiología , Masculino , Enfermedad de Parkinson Secundaria/inducido químicamente , Equilibrio Postural/fisiología , Ratas , Ratas Wistar , Percepción Espacial/fisiología , Técnicas Estereotáxicas , Trihexifenidilo/administración & dosificaciónRESUMEN
Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.
Asunto(s)
Ganglios Basales/fisiología , Dopamina/fisiología , Discinesias/fisiopatología , Animales , Ganglios Basales/citología , Recuento de Células , Desnervación , Electrofisiología , Espacio Extracelular/enzimología , Hidroxidopaminas , Inmunohistoquímica , Masculino , Mesencéfalo/fisiología , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/patología , Sustancia Negra/fisiología , Simpatectomía Química , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
It is known that the inhibition of Na+,K(+)-ATPase induces neurotransmitter release in several experimental models. In this laboratory it was previously observed that a brain soluble fraction separated by Sephadex G-50 (peak II) is able to inhibit Na+,K(+)-ATPase but not other membrane-bound enzymes. The object of the present study was to test the effect of brain peak II fraction on neurotransmitter content of the pineal nerves synaptic vesicles. Uninjected rats and rats injected 30 min before with 5-hydroxydopamine (30 mg per kg,i.p.) were used. 5-hydroxydopamine produces a false neurotransmitter whose presence in the synaptic vesicles is visualized after fixation with glutaraldehyde-osmium as an electron dense material with the electron microscope which fills totally or partially the vesicles. In uninjected rats the osmiophilia and the chromaffin reaction of the electron dense core were studied. The pineal glands were incubated in Tyrode solution without calcium in the presence and absence of peak II at room temperature and processed for electron microscopy. When the glands from rats pretreated with 5-hydroxydopamine were incubated with peak II a significant decrease in the number of vesicles totally stained was observed. This indicates a reduction in false neurotransmitter content, specially in the matrix of the synaptic vesicles. In the presence of an aged peak II, which does not inhibit Na+,K(+)-ATPase, this effect on the synaptic vesicles was not observed. When the glands from uninjected rats were incubated with peak II no changes in the osmiophilia and the chromaffin reaction of the synaptic vesicles were found. The osmiophilia and the chromaffin reaction of the cores marks the monoamines storage site (catechol and indoleamines in the pineal nerves). These results are coherent with the idea of a relationship between the inhibition of Na+,K(+)-ATPase activity and the release of a pool of neurotransmitter stored in the nerve endings.
Asunto(s)
Química Encefálica , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Neurotransmisores/metabolismo , Norepinefrina/metabolismo , Glándula Pineal/efectos de los fármacos , Serotonina/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Animales , Cromatografía en Gel , Hidroxidopaminas/farmacocinética , Microscopía Electrónica , Neuronas/enzimología , Neuronas/metabolismo , Glándula Pineal/ultraestructura , Ratas , Vesículas Sinápticas/química , Vesículas Sinápticas/ultraestructura , Extractos de Tejidos/farmacologíaRESUMEN
Se ha demostrado que la inhibición de la Na+, K+-ATPasa produce liberación de neurotransmisor en distintos modelos experimentales. En este laboratorio se observó previamente que una fracción soluble separada mediante Sephadex G-50 (pico II) es capaz de inhibir la actividad de Na+, K+-ATPasa pero no de otras enzimas asociadas a membranas. El objetivo del presente trabajo fue probar el efecto de la fracción pico II de cerebro sobre el contenido de neurotransmisor de las vesículas sinápticas de los nervios pineales. Se usaron ratas no inyectadas y ratas inyectadas 30 min antes con 5-hidroxidopamina (30 mg per Kg, i.p.). La 5-hidroxidopamina produce un falso neurotransmisor cuya presencia en las vesículas sinápticas se visualiza luego de la fijación con glutaraldehído-osmio como un material electrón denso que llena total o parcialmente las vesículas. En ratas no inyectadas se estudió la osmiofilia y la reacción cromafín del nucleoide electron denso. Las glándulas pineales se incubaron en solución Tyrode sin calcio en presencia y ausencia de pico II a temperatura ambiente y se estudiaron al microscopio electrónico. Cuando las glándulas de las ratas pretratadas con 5-hidroxidopamina se incubaron con pico II se observó una disminución siginificativa en el número de vesículas totalmente llenas de material electrón denso. Esto indica una reducción en el contenido de falso neurotransmisor contenido en la matriz de las vesículas sinápticas. Este efecto sobre las vesículas sinápticas no se observó en presencia de pico II invejecido, que no inhibe la Na+, K+-ATPasa. Cuando las gládulas de ratas no inyectadas se incubaron con pico II no se observaron cambios ni en la osmiofilia ni en la reacción cromafin de las vesículas sinápticas. La osmiofilia y la reacción cromafin del nucleoide electrón denso marca el sitio de acumulación de monoaminas (catecol e indolaminas en los nervios pineales). Estos resultados son coherentes con la idea de una relación entre la inhibición de la actividad de Na+, K+-ATPasa y la liberación de una fracción de neurotransmisor acumulado en los terminales nerviosos (AU)
Asunto(s)
Animales , Ratas , Química Encefálica , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Neurotransmisores/metabolismo , Norepinefrina/metabolismo , Glándula Pineal/efectos de los fármacos , Serotonina/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Cromatografía en Gel , Hidroxidopaminas/farmacocinética , Microscopía Electrónica , Neuronas/enzimología , Neuronas/metabolismo , Glándula Pineal/ultraestructura , Vesículas Sinápticas/química , Vesículas Sinápticas/ultraestructura , Extractos de Tejidos/farmacologíaRESUMEN
Se ha demostrado que la inhibición de la Na+, K+-ATPasa produce liberación de neurotransmisor en distintos modelos experimentales. En este laboratorio se observó previamente que una fracción soluble separada mediante Sephadex G-50 (pico II) es capaz de inhibir la actividad de Na+, K+-ATPasa pero no de otras enzimas asociadas a membranas. El objetivo del presente trabajo fue probar el efecto de la fracción pico II de cerebro sobre el contenido de neurotransmisor de las vesículas sinápticas de los nervios pineales. Se usaron ratas no inyectadas y ratas inyectadas 30 min antes con 5-hidroxidopamina (30 mg per Kg, i.p.). La 5-hidroxidopamina produce un falso neurotransmisor cuya presencia en las vesículas sinápticas se visualiza luego de la fijación con glutaraldehído-osmio como un material electrón denso que llena total o parcialmente las vesículas. En ratas no inyectadas se estudió la osmiofilia y la reacción cromafín del nucleoide electron denso. Las glándulas pineales se incubaron en solución Tyrode sin calcio en presencia y ausencia de pico II a temperatura ambiente y se estudiaron al microscopio electrónico. Cuando las glándulas de las ratas pretratadas con 5-hidroxidopamina se incubaron con pico II se observó una disminución siginificativa en el número de vesículas totalmente llenas de material electrón denso. Esto indica una reducción en el contenido de falso neurotransmisor contenido en la matriz de las vesículas sinápticas. Este efecto sobre las vesículas sinápticas no se observó en presencia de pico II invejecido, que no inhibe la Na+, K+-ATPasa. Cuando las gládulas de ratas no inyectadas se incubaron con pico II no se observaron cambios ni en la osmiofilia ni en la reacción cromafin de las vesículas sinápticas. La osmiofilia y la reacción cromafin del nucleoide electrón denso marca el sitio de acumulación de monoaminas (catecol e indolaminas en los nervios pineales). Estos resultados son coherentes con la idea de una relación entre la inhibición de la actividad de Na+, K+-ATPasa y la liberación de una fracción de neurotransmisor acumulado en los terminales nerviosos
Asunto(s)
Animales , Ratas , Neuronas , Neurotransmisores/metabolismo , Norepinefrina/metabolismo , Glándula Pineal/efectos de los fármacos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Química Encefálica , Serotonina/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Cromatografía en Gel , Hidroxidopaminas/farmacocinética , Microscopía Electrónica , Neuronas/enzimología , Neuronas , Glándula Pineal/ultraestructura , Extractos de Tejidos/farmacología , Vesículas Sinápticas/química , Vesículas Sinápticas/ultraestructuraRESUMEN
Vanadate is a potent inhibitor of calcium stimulated ATPase, Na, K-ATPase, and may have adrenergic activity. Using the iontophoresis method, we compared vanadate to a BSS control and the standard iontophoresis model (6-hydroxydopamine/epinephrine) by measuring induced ocular shedding of latent HSV-1 in different host animals. Latent trigeminal ganglionic infections were established in Balb/c mice and New Zealand rabbits following corneal inoculation with HSV-1 [W] strain, and later confirmed by cocultivation. Latently-infected animals (greater than 1 month post-infection) were divided into three treatment groups. Each group was iontophoresed with BSS, vanadate 1% or 6-HD 1%, and then treated topically for 10 days with BSS, vanadate or epinephrine respectively. Reactivation and recovery of latent HSV-1 was detected by daily ocular swabbing, plating, and observing progressive viral growth in Vero cells. The vanadate group had more virus-positive eyes than the BSS control group in mice, (8/32 vs. 1/32 P less than .01), and also in rabbits (14/20 vs 6/22 P less than .01). Virus-positive animals and total positive swabs were also higher for vanadate than BSS in both mice and rabbits. Furthermore, while vanadate was associated with fewer virus-positive eyes than 6-HD & EPI (8/32 vs. 17/32 P less than .02) in mice, there were no significant differences in rabbits. We conclude that vanadate promotes ocular shedding of latent HSV-1, and may act through an adrenergic mechanism.
Asunto(s)
Ojo/microbiología , Simplexvirus/efectos de los fármacos , Vanadatos/farmacología , Activación Viral/efectos de los fármacos , Animales , Células Cultivadas , Distribución de Chi-Cuadrado , Córnea/microbiología , Epinefrina/farmacología , Femenino , Hidroxidopaminas/farmacología , Iontoforesis , Masculino , Ratones , Ratones Endogámicos BALB C , Oxidopamina , Conejos , Simplexvirus/crecimiento & desarrollo , Simplexvirus/aislamiento & purificación , Lágrimas/microbiología , Ganglio del Trigémino/microbiología , Células Vero , Cultivo de VirusRESUMEN
The effect of a lack of dopamine (DA) in the striatum upon the K(+)-evoked release of cholecystokinin (CCK) from superfused rat striatal slices has been studied. Two pharmacological tools were used to deplete the nigrostriatal DA system: administration of alpha-methyl-p-tyrosine which competitively inhibits DA synthesis and lesions with 6-hydroxydopamine of the medial forebrain bundle. In both cases there was a significant inhibition of the K(+)-evoked release of CCK. The observed effects might be relevant on pathological conditions implying depletion of the DA system.
Asunto(s)
Colecistoquinina/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/fisiología , Potasio/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Dopamina/metabolismo , Hidroxidopaminas , Técnicas In Vitro , Masculino , Metiltirosinas/farmacología , Neurotoxinas , Oxidopamina , Ratas , Ratas Endogámicas , alfa-MetiltirosinaRESUMEN
IV bolus administration of 2.5-50 micrograms NPY (0.6-12.5 nmol) to conscious rats produced a dose- and time-dependent increase in systolic and diastolic blood pressure. Following priming with 2.5 micrograms NPY, or larger doses, the subsequent administrations of noradrenaline produced pressor responses that were potentiated both in magnitude and duration. The NPY-induced potentiation of the pressor response to noradrenaline was dose-dependent and extended to the pressor action of adrenaline and angiotensin II but not to the hypotensions produced by bradykinin or isoproterenol. The potentiation was not related to the fact that multiple doses of catecholamines were repeated. Reserpine did not substantially modify the NPY-induced potentiation of the pressor activity of the catecholamines. Chemical sympathectomy following 6-hydroxydopamine caused a marked supersensitivity to the catecholamines and NPY but obliterated the NPY-induced potentiation of the pressor effect of adrenaline. Nifedipine reduced the pressor action of the catecholamines and NPY but did not attenuate the NPY-induced potentiation of the pressor action of catecholamines. It is concluded that the acute pressor effect of NPY and of the potentiation of the catecholamine pressor effects involve different mechanisms.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Epinefrina/farmacología , Neuropéptido Y/farmacología , Norepinefrina/farmacología , Animales , Antihipertensivos/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Hexametonio , Compuestos de Hexametonio/farmacología , Hidroxidopaminas/farmacología , Masculino , Nifedipino/farmacología , Oxidopamina , Ratas , Ratas Endogámicas , Valores de Referencia , Reserpina/farmacologíaRESUMEN
The influence of 6-hydroxydopamine (6-OHDA) pretreatment on xylazine (XLZ)-induced antinociception was studied in mice using the writhing test (60 mg/kg acetic acid, ip, as the algogenic compound administered 10 min after 0.5 and 0.75 mg/kg XLZ, sc). 6-OHDA (100 mg kg-1 injection-1 administered ip on days 1, 3, 5, 7, 9 and 11 after birth) did not modify XLZ-induced antinociception, suggesting that this effect is mediated by postsynaptic alpha-2 adrenoceptors.
Asunto(s)
Analgesia , Hidroxidopaminas/uso terapéutico , Dimensión del Dolor/efectos de los fármacos , Tiazinas/farmacología , Xilazina/farmacología , Animales , Masculino , Ratones , Neuronas/efectos de los fármacos , Oxidopamina , Receptores Adrenérgicos alfa/metabolismoRESUMEN
The effects of the antipsychotic drug haloperidol (HAL) on the electrophysiological activity of dopamine (DA)-containing cells in the substantia nigra was assessed in rats 6 weeks after partial 6-hydroxydopamine (6-OHDA)-induced lesions of the nigrostriatal DA pathway. Depleting 75% or more of striatal DA altered the response of DA neurons to acute HAL administration. Whereas acute HAL administration generally accelerates DA neuron firing in control rats, similar HAL doses given to lesioned rats not only increased firing rate but induced depolarization block of DA neuron spike generation similar to that resulting from chronic neuroleptic administration. In contrast, acute administration of doses of HAL up to lethal levels typically could not induce depolarization block of DA neurons in non-lesioned rats. This preparation thus could be an effective model for investigating the exacerbation of behavioral deficits produced by an increased demand placed upon a compromised DA system, as may occur in Parkinson's disease or with antipsychotic drug treatment.
Asunto(s)
Haloperidol/farmacología , Hidroxidopaminas , Sustancia Negra/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Oxidopamina , Ratas , Ratas Endogámicas , Sustancia Negra/efectos de los fármacosRESUMEN
The turning or circling activity of the rat is a very useful experimental model for the study of dopaminergic cerebral pathways. Quantification of turning makes it applicable to follow changes of pattern evolution in the same subject or for comparison between animals under different experimental conditions. Automated quantitative evaluation of turning has the advantage of its reliability, eliminates subjective inaccuracies and allows longer periods of observation. Therefore a fully automated rotometer aimed to accomplish these objectives was developed. It consists of a sensor box to transduce the circling movement of animals into computed information to be processed by a microprocessor and a printer for recording of results. The sensor was designed with a 16 holes perforated disc and two infrared receiver/emitter units. Pulses generated in the sensor box are computed and stored by the microprocessor. Reading of results may be made in manual or automated mode from the display or listed through the printer connected on-line. The reliability and validity of the rotometer were tested in animals submitted to different experimental conditions. Rats with unilateral chemical lesions (6-hydroxy-dopamine or kainic acid) of substantia nigra pars compacta rotated vigorously contraversive to lesion side after apomorphine injection (0.5 and 1 mg/kg, s.c.). Electrolytic lesion of the same nucleus made animals rotate ipsiversive to the lesion after apomorphine. To attain significant level of circling activity, the electrolytic lesion should be placed in the external boundaries of substantia nigra (265.8 +/- 53.4 turns/60 min for group with external placed lesion; (n = 5); 97.3 +/- 19.5 for group with internal placed lesion (n = 3); t = 2.31; p less than 0.05). Unilateral striatal lesion with ibotenic acid made animals rotate ipsilaterally with apomorphine as well as with the selective D-2 agonist bromocriptine (10 and 30 mg/kg, i.p.). Qualiquantitative differences in circling were observed between these two dopaminergic agonists. Comparison of circling activity on semispherical and flat surfaces showed a non significant trend to rotate more intensively on spherical surfaces but only in those animals turning greater than or equal to 3 turns/min. The results obtained with the automated rotometer herein described agree with those currently reported in the literature about the subject. They demonstrate also that this apparatus is adequate and reliable for the study of turning behavior under different experimental conditions. Interestingly enough, our observation on the specificity of electrolytic lesions placed in the lateral boundaries of substantia nigra to induce rotation is worth further investigation.
Asunto(s)
Dopaminérgicos/farmacología , Actividad Motora , Conducta Estereotipada , Sustancia Negra/fisiología , Animales , Apomorfina/farmacología , Bromocriptina/farmacología , Femenino , Hidroxidopaminas/farmacología , Ácido Kaínico/farmacología , Masculino , Oxidopamina , Ratas , Ratas Endogámicas , Sustancia Negra/efectos de los fármacosRESUMEN
The effects of 6-hydroxydopamine (6-OHDA) i.c.v. on ethanol-induced narcosis were studied in mice, either untreated or pretreated with alpha-methyl-p-tyrosine (AMPT), p-chlorophenylalanine (PCPA) or 5-hydroxytryptophan (5-HTP). Mice treated with 6-OHDA 200 micrograms i.c.v., exhibited longer ethanol narcosis time than untreated controls. This effect was significantly increased when mice treated with 6-OHDA received AMPT (inhibitor of catecholamine biosynthesis) or 5-HTP (precursor or serotonin biosynthesis). After administration of PCPA (inhibitor of tryptophan hydroxylase) 6-OHDA did not prolong ethanol narcosis. Alcohol blood levels at awakening time were not significantly influenced by 6-OHDA. These results are consistent with the idea that a decrease in brain noradrenaline as well as an increase in brain serotonin enhance the narcotic action of ethanol, while both, the increase in brain noradrenaline and the decrease in brain serotonin shorten ethanol narcosis.
Asunto(s)
Etanol/farmacología , Hidroxidopaminas/farmacología , Fases del Sueño/efectos de los fármacos , Análisis de Varianza , Animales , Femenino , Fenclonina/farmacología , Inyecciones Intraventriculares , Masculino , Metiltirosinas/farmacología , Ratones , Oxidopamina , Antagonistas de la Serotonina/farmacología , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , alfa-MetiltirosinaRESUMEN
1. Twenty-eight male albino rats were evaluated for audiogenic seizure sensitivity by systematic observation and the recording of behavior by ethological methods. The animals were subjected to high-intensity acoustic stimulation and their behavior was evaluated by reference to an audiogenic severity index (SI). Animals were classified as susceptible (S) or resistant (R) depending on the SI value. R animals were: 1) subjected to chemical lesion of the substantia nigra compacta with 6-hydroxydopamine (6OHDA), followed by SI quantitation, contralateral electrolytic lesion of the substantia nigra reticulata and new SI evaluation (N = 6); 2) a group of control animals (N = 10) received 0.9% saline followed by SI evaluation, contralateral sham (mechanical) lesion and new SI calculation; 3) another group (N = 10) was subjected to unilateral electrolytical lesion of the substantia nigra reticulata and SI evaluation. 2. Effects of asymmetry were observed after chemical or electrolytic lesions, but these alterations correlated only with increased audiogenic sensitivity in rats with electrolytic lesions in the substantia nigra reticulata. No behavioral changes were observed in any of the controls. The amphetamine-induced rotational behavior presented a definite left pattern (ipsilateral to the 6OHDA lesion) for the animals with bilateral lesions, with an asymmetry index of 98%, whereas the sham-lesioned controls showed a 60% asymmetry index which was not significant. 3. The relationship between asymmetry and simultaneous audiogenic sensitivity may correspond to changes in the basal ganglia possibly in the hypersensitive postsynaptic portions of the substantia nigra reticulata efferents.
Asunto(s)
Conducta Animal , Hidroxidopaminas/farmacología , Convulsiones/etiología , Sustancia Negra/fisiología , Estimulación Acústica , Animales , Electrólisis , Lateralidad Funcional , Masculino , Oxidopamina , Ratas , RotaciónRESUMEN
Se describe un rotámetro totalmente automático destinado a la cuantificación del comportamiento rotatorio en ratas con lesión unilateral del sistema nigroestiado. Las partes fundamentales del rotámetro son: a) sensor compuesto a su vez por un disco perforado que reproduce la rotación del animal mediante giro homólogo y dos células infrarrojo, con emisor y receptor cada una de ellas; b) microprocesador que transforma los pulsos de las células fotoeléctricas en información computadorizada, memoriándola; c) impressora comercial conectada al microprocesador. La confiabilidad, utilidad y validez del rotámetro se ensayó en distintos grupos experimentales de ratas adultas. La destrucción unilateral de la zona compacta de la sustantia nigra con 6-hidroxidopamina o ácido Kaínico intracerebrales, produce rotación contralateral bajo administración de apomorfina (0.5 y 1 mg/Kg, s.c.). En cambio la apomorfina provoca rotación homólateral a la lesión en animales con destrucción electrolítica (1.5 mA, 15 s) de la nigra. Para obtener una actividad rotatoria significativa, la lesión electrolítica debe ubicarse en la región externa del núcleo (365+53.4 vueltas/60m en lesión externa (n=5); 97.3ñ19.5 en lesión interna (n=3); t=2.31, p<0,05. Apomorfina 0.5 mg/Kg, s.c.). En animales con lesión unilateral del caudado por ácido iboténico intracerebral, se observa rotación homolateral tanto a la apomorfina como a la bromocriptina tanto a la apomorfina como a la bromocriptina (10 y 30 mg/Kg, i.p.). Se comprueban dif
Asunto(s)
Ratas , Animales , Masculino , Femenino , Estudio Comparativo , Conducta Estereotipada , Rotación , Procesamiento Automatizado de Datos , Sustancia Negra/fisiología , Dopaminérgicos/farmacología , Apomorfina/farmacología , Hidroxidopaminas/farmacología , Bromocriptina/farmacología , Ácido Kaínico/farmacología , Ratas EndogámicasRESUMEN
Se estudian los efectos de la administración de 6-hidroxidopamina (6-OHDA0, 100 Y 200 microng i.c.v., en la duración de la narcosis por etanol en ratones sin o con tratamiento de alfa-metil-p-tirosina (AMPT), p-cloro-fenilalanina (PCPA) o 5-hidroxitriptófano (5-HTP). La narcosis por etanol fue significativamente más prolongada en los ratones que recibieron 200 microng de 6-OHDA i.c.v. que en los testigos. La duración de la narcosis en los ratones tratados con ambas dosis de 6-OHDA fue significativamente más larga cuando éstos recibieron previamente AMPT (inhibidor de la biosíntesis de seotonina). En 5-HTP (precursor de la biosíntesis de serotonina). En cambio, en los pretratados con PCPA (inhibidor de la triptófano hidroxilasa), la 6-OHDA no modificó la duración de la narcosis por etanol. Las alcoholemias al momento de despertar no cambiaron significativamente por la 6-OHDA. Estos resultados son consistentes con la hipótesis de que la disminución de noradrenalina así como el aumento de serotonina cerebrales prolongan la narcosis por etanol y, en cambio, el aumento de noradrenalina o la disminución de serotonina en el cerebro reducen la narcosis por etanol (AU)