RESUMEN
L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.
Asunto(s)
Catecol O-Metiltransferasa/metabolismo , Levodopa/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Inhibidores de Catecol O-Metiltransferasa , Catecoles/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Inhibidores Enzimáticos/farmacología , Levodopa/antagonistas & inhibidores , Metionina/farmacología , Neuronas/citología , Ratas , S-Adenosilmetionina/farmacologíaRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of Alzheimer's disease, although the underlying mechanisms are unknown. Glutamate excitotoxicity has been implicated in Alzheimer's disease, Parkinson's disease, and others. We examined the effects of aspirin, acetaminophen, and ibuprofen on cultured primary rat embryonic neurons from mesencephalon, the area primarily affected in Parkinson's disease. We evaluated whether these drugs protect dopaminergic neurons against excitotoxicity. All three NSAIDs significantly attenuated the decrease in dopamine uptake caused by glutamate, indicating preservation of neuronal integrity. One hundred micro-moles ibuprofen protected both dopaminergic neurons and neurons overall against glutamate toxicity. In addition, ibuprofen alone increased the relative number of dopaminergic neurons by 47%. Thus, NSAIDs protected neurons against glutamate excitotoxicity in vitro, and deserve further consideration as neuroprotective agents in Parkinson's disease.
Asunto(s)
Dopamina/metabolismo , Ácido Glutámico/efectos adversos , Ácido Glutámico/efectos de los fármacos , Ibuprofeno/farmacología , Mesencéfalo/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Neurotoxinas/antagonistas & inhibidores , Acetaminofén/farmacología , Animales , Aspirina/farmacología , Recuento de Células/estadística & datos numéricos , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Células Cultivadas/patología , Feto , Mesencéfalo/patología , Mesencéfalo/fisiopatología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , RatasRESUMEN
The alpha4-subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR) subunit family has recently been identified in two families as the gene responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare monogenic idiopathic epilepsy. As a result of this finding, other subunits of the neuronal nAChR gene family are being considered as candidate genes for ADNFLE in families not linked to CHRNA4 and for other idiopathic epilepsies. Alpha4-subunits often assemble together with beta2-subunits (gene symbol CHRNB2) to build heteromeric nAChRs. The gene encoding another abundant AChR subunit, the alpha3-subunit gene (CHRNA3), is present with those encoding two other subunits, CHRNB4 and CHRNA5, in a gene cluster whose functional role is still unclear. Here we provide the information on the genomic structures of both the CHRNB2 and the CHRNA3 genes that is necessary for comprehensive mutational analyses, and we refine the genomic assignment of CHRNB2 on chromosome 1.
Asunto(s)
Epilepsia del Lóbulo Frontal/genética , Receptores Nicotínicos/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 1 , Análisis Mutacional de ADN , Exones , Humanos , Hibridación Fluorescente in Situ , Intrones , Masculino , Datos de Secuencia Molecular , Neuronas , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Análisis de Secuencia de ADN , Repeticiones de TrinucleótidosRESUMEN
The locomotor hyperactivity induced by 3,4-methylene-dioxymethamphetamine (MDMA) and related drugs in rats appears to be due to the drug-induced release of presynaptic serotonin (5-HT). Thus, these drugs increase locomotor activity by acting as indirect 5-HT agonists. The subtype of 5-HT receptor upon which this released 5-HT acts postsynaptically to produce the activating effect of MDMA-like drugs is not known. When tested under conditions in which MDMA increases locomotion, direct agonists at both 5-HT1A and 5-HT1C/2 receptors consistently decrease locomotion. Hence, the present experiments tested the hypothesis that the hyperactivity produced by the release of endogenous 5-HT is due to the activation of 5-HT1B receptors. Using the Behavioral Pattern Monitor (BPM), the profile of behavioral effects of a 5-HT1B agonist, 5-methoxy-3(1,2,3,6)tetrahydropyridin-4yl)-1H-indole (RU 24969), was compared to that previously described for MDMA and related indirect 5-HT agonists. The BPM provided detailed information regarding the amount and qualitative patterning of locomotor activity and investigatory responses in rats. Various doses of RU 24969 (1.25 to 5 mg/kg) were administered to naive male rats 10 minutes prior to placement in the test chambers. As previously reported for MDMA, locomotor activity increased with dose, and investigatory rearings and holepokes decreased. The hyperactivity was characterized by repetitive spatial patterns of locomotion that were qualitatively similar to those produced by indirect 5-HT agonists such as MDMA and dissimilar to those produced by indirect dopamine (DA) agonists such as amphetamine. Pretreatment with racemic propranolol but not (+)propranolol antagonized the hyperactivity induced by RU 24959. Fluoxetine, a 5-HT reuptake inhibitor, failed to block the locomotor activating effects of RU 24969. These findings confirm the similarity between the behavioral effects of RU 24969 and indirect 5-HT agonists and suggest that the locomotor hyperactivity produced by both RU 24969 and MDMA is mediated by the activation of 5-HT1B receptors. Although the effects of MDMA on 5-HT1B receptors are secondary to its ability to release presynaptic 5-HT, the activation produced by RU 24969 appears to be a consequence of its direct agonist effects.
Asunto(s)
Conducta Animal/fisiología , Indoles/farmacología , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Serotonina/metabolismo , Sinapsis/metabolismo , 3,4-Metilenodioxianfetamina/análogos & derivados , 3,4-Metilenodioxianfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Cafeína/farmacología , Drogas de Diseño/farmacología , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Fluoxetina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina , Nicotina/farmacología , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Escopolamina/farmacología , Sinapsis/efectos de los fármacosRESUMEN
Recent work has been directed at identifying the critical components of the medial temporal lobe that, when damaged, produce severe memory impairment. The H+A+ lesion includes the hippocampal formation, the amygdala, and the adjacent entorhinal, parahippocampal, and perirhinal cortices. A more restricted medial temporal lobe lesion that includes the hippocampal formation and parahippocampal cortex (the H+ lesion) produces less severe memory impairment. Previous work demonstrated that extending the H+ lesion forward to include the amygdala did not exacerbate the impairment. Here, we tested the hypothesis that extending the H+ lesion forward to include the perirhinal cortex (the H++ lesion), but sparing the amygdala, should produce a more severe memory impairment and one that would approximate the level of memory impairment associated with the H+A+ lesion. Monkeys with the H++ lesion were severely impaired on two of three amnesia-sensitive tasks (delayed nonmatching to sample and delayed retention of object discrimination). On the third amnesia-sensitive task (concurrent discrimination learning), two of the monkeys in the H++ group obtained poorer scores than all seven normal monkeys, although the overall group comparison was not significant. The memory impairment following H++ damage was more severe overall than the impairment associated with the H+ lesion and approached the level of impairment associated with the H+A+ lesions. Quantitative measurement of damage in each anatomical component of the lesion indicated that the perirhinal cortex was the only brain region that was more extensively damaged in the H++ group than in the H+ group. These findings emphasize the importance of the perirhinal cortex in the anatomy of the medial temporal lobe memory system.
Asunto(s)
Hipocampo/fisiología , Sistema Límbico/fisiología , Memoria/fisiología , Animales , Conducta Animal/fisiología , Mapeo Encefálico , Discriminación en Psicología/fisiología , Macaca fascicularis , Actividad Motora/fisiología , Retención en Psicología/fisiología , Factores de TiempoRESUMEN
This study was designed to evaluate the role of different serotonin (5-HT) receptor subtypes in mediating the effects of 3,4-methylenedioxymethamphetamine (MDMA) on rat exploration of a novel environment. The active enantiomer of MDMA, S-MDMA increases forward locomotion and suppresses investigatory behaviors and local movements. Previous studies indicate that S-MDMA-induced hyperactivity depends upon drug-induced 5-HT release. Propranolol and pindolol, beta-noradrenergic antagonists with affinity for 5-HT1 receptors, antagonized the S-MDMA-induced locomotor hyperactivity. The antagonism by propranolol was stereoselective. In contrast, a beta-noradrenergic antagonist that is a weaker antagonist of 5-HT receptors, betaxolol, was much less effective at blocking the behavioral response to S-MDMA. Among nonselective 5-HT antagonists, methiothepin was effective and methysergide and cyproheptadine were ineffective as antagonists of S-MDMA-induced hypermotility. In other systems, methiothepin has been found to be a good antagonist at 5-HT1B receptors where methysergide and cyproheptadine are ineffective. The 5-HT2 antagonist ritanserin was ineffective in blocking S-MDMA-induced hypermotility. However, ritanserin, methysergide, and cyproheptadine partially reversed the S-MDMA-induced suppression of investigatory responding, suggesting a contribution of 5-HT2 receptor activation to this component of the behavioral response to S-MDMA. This study indicates that S-MDMA produces a characteristic form of locomotor hyperactivity in rats that depends upon activation of 5-HT1-like receptors, possibly of the 5-HT1B subtype.
Asunto(s)
3,4-Metilenodioxianfetamina/análogos & derivados , Actividad Motora/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , 3,4-Metilenodioxianfetamina/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Conducta Animal/efectos de los fármacos , Masculino , N-Metil-3,4-metilenodioxianfetamina , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/farmacologíaRESUMEN
Patient RB became amnesic following an episode of global ischemia that resulted in a bilateral lesion of the CA1 field of the hippocampus. This finding suggested that damage restricted to the hippocampus is sufficient to produce clinically significant memory impairment. To evaluate further the effect of ischemic brain damage on memory, we have developed an animal model of cerebral ischemia in the monkey. Monkeys were subjected to 15 min of reversible ischemia, using a noninvasive technique involving carotid occlusion and pharmacologically induced hypotension. These monkeys sustained significant loss of pyramidal cells in the CA1 and CA2 fields of the hippocampus, as well as loss of somatostatin-immunoreactive cells in the hilar region of the dentate gyrus. Cell loss occurred bilaterally throughout the rostrocaudal extent of the hippocampus but was greater in the caudal portion. Except for patchy loss of cerebellar Purkinje cells, significant damage was not detected in areas outside the hippocampus, including adjacent cortical regions, that is, entorhinal, perirhinal, and parahippocampal cortex, and other regions that have been implicated in memory function. On behavioral tests, the ischemic monkeys exhibited significant and enduring memory impairment. On the delayed nonmatching to sample task, the ischemic monkeys were as impaired as monkeys with lesions of the hippocampal formation and adjacent parahippocampal cortex (the H+ lesion). On two other memory tasks, the ischemic monkeys were less impaired than monkeys with the H+ lesion. In neuropathological evaluations, it has always been difficult to rule out the possibility that significant areas of neuronal dysfunction have gone undetected. The finding that ischemic lesions produced overall less memory impairment than H+ lesions indicates that the ischemic monkeys (and by extension, patient RB) are unlikely to have widespread neuronal dysfunction affecting memory that was undetected by histological examination. These results provide additional evidence that the hippocampus is a focal site of pathological change in cerebral ischemia, and that damage limited to the hippocampus is sufficient to impair memory.
Asunto(s)
Amnesia/fisiopatología , Isquemia Encefálica/psicología , Hipocampo/irrigación sanguínea , Memoria/fisiología , Amnesia/etiología , Animales , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Electroencefalografía , Hipocampo/patología , Hipocampo/fisiología , Macaca fascicularis , Tractos Piramidales/patología , Tractos Piramidales/fisiología , Tractos Piramidales/fisiopatología , Valores de Referencia , Factores de TiempoRESUMEN
Only a small proportion of ewes at estrus have been found to respond maternally to newborn lambs, and this low maternal responsiveness may be partially attributable to the absence of the genital stimulation which occurs at parturition. Therefore, the effect of artificial genital stimulation on maternal behavior of estrous ewes was investigated. Estrus was synchronized in 33 ewes by placement and withdrawal of progestin-saturated vaginal sponges. Estrous ewes were divided into two groups, a control group and a group receiving 5 min of artificial genital stimulation, and observed following presentation of newborn lambs. Significantly more stimulated ewes licked the lamb and emitted low-pitched bleats in a 30-min test. When genital stimulation was subsequently administered to control ewes, more of them also became maternal so that the two groups were no longer significantly different. These results indicate that absence of genital stimulation is one of the factors contributing to the low maternal responsiveness of estrous ewes. They also demonstrate for the first time that artificial genital stimulation is effective in eliciting maternal behavior in nonpregnant ewes even at physiological concentrations of estradiol.