RESUMEN
Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-aged wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/metabolismo , Demencia Frontotemporal/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neuronas/metabolismo , Animales , Encéfalo/patología , Recuento de Células , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Granulinas , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Neuronas/patología , ProgranulinasRESUMEN
There has been a growing controversy regarding the continued use of glucocorticoid therapy to treat respiratory dysfunction associated with prematurity, as mounting clinical evidence has shown neonatal exposure produces permanent neuromotor and cognitive deficits. Here we report that, during a selective neonatal window of vulnerability, a single glucocorticoid injection in the mouse produces rapid and selective apoptotic cell death of the proliferating neural progenitor cells in the cerebellar external granule layer and permanent reductions in neuronal cell counts of their progeny, the cerebellar internal granule layer neurons. Our estimates suggest that this mouse window of vulnerability would correspond in the human to a period extending from approximately 20 weeks gestation to 6.5 weeks after birth. This death pathway is critically regulated by the proapoptotic Bcl-2 family member Puma and is independent of p53 expression. These rodent data indicate that there exists a previously unknown window of vulnerability during which a single glucocorticoid exposure at clinically relevant doses can produce neural progenitor cell apoptosis and permanent cerebellar pathology that may be responsible for some of the iatrogenically induced neurodevelopmental abnormalities seen in children exposed to this drug. This vulnerability may be related to the physiological role of glucocorticoids in regulating programmed cell death in the mammalian cerebellum.
Asunto(s)
Apoptosis/efectos de los fármacos , Cerebelo/crecimiento & desarrollo , Glucocorticoides/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Células Madre/efectos de los fármacos , Células Madre/fisiología , Animales , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis , Conducta Animal/fisiología , Cerebelo/citología , Niño , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/fisiología , Neuronas/citología , Transducción de Señal/fisiología , Células Madre/citología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.
Asunto(s)
Maleato de Dizocilpina/antagonistas & inhibidores , Neurotoxinas/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Barbitúricos/farmacología , Embrión de Pollo , Parasimpatolíticos/farmacología , Pilocarpina/farmacología , Ratas , Escopolamina/farmacología , Vacuolas/ultraestructuraRESUMEN
The deleterious effects of ethanol on the developing human brain are poorly understood. Here it is reported that ethanol, acting by a dual mechanism [blockade of N-methyl-D-aspartate (NMDA) glutamate receptors and excessive activation of GABA(A) receptors], triggers widespread apoptotic neurodegeneration in the developing rat forebrain. Vulnerability coincides with the period of synaptogenesis, which in humans extends from the sixth month of gestation to several years after birth. During this period, transient ethanol exposure can delete millions of neurons from the developing brain. This can explain the reduced brain mass and neurobehavioral disturbances associated with human fetal alcohol syndrome.
Asunto(s)
Etanol/toxicidad , Trastornos del Espectro Alcohólico Fetal/patología , Degeneración Nerviosa , Prosencéfalo/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Apoptosis , Benzodiazepinas/farmacología , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Etanol/sangre , Femenino , Moduladores del GABA/farmacología , Humanos , Neuronas/citología , Neuronas/patología , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Prosencéfalo/citología , Prosencéfalo/embriología , Prosencéfalo/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
Stress and exploration of novel environments induce neural expression of immediate early gene transcription factors (IEG-TFs). However, as yet no IEG-TF has been shown to be required for the normal biological or behavioral responses to these stimuli. Here we show that mice deficient for the IEG-TF early growth response gene (Egr) 3, display accentuated behavioral responses to the mild stress of handling paralleled by increased release of the stress hormone corticosterone. Egr3-/- mice also display abnormal responses to novelty, including heightened reactivity to novel environments and failure to habituate to social cues or startling acoustic stimuli. In a Y-maze spontaneous alternation task, they perform fewer sequential arm entries than controls, suggesting defects in immediate memory. Because stress and novelty stimulate hippocampal long-term depression (LTD), and because abnormalities in habituation to novelty and Y-maze performance have been associated with LTD deficits, we examined this form of synaptic plasticity in Egr3-/- mice. We found that Egr3-/- mice fail to establish hippocampal LTD in response to low frequency stimulation and exhibit dysfunction of an ifenprodil-sensitive (NR1/NR2B) N-methyl-d-aspartate receptor subclass. Long term potentiation induction was not altered. The NR2B-dependent dysfunction does not result from transcriptional regulation of this subunit by Egr3, because NR2B mRNA levels did not differ in the hippocampi of Egr3-/- and control mice. These findings are the first demonstration of the requirement for an IEG-TF in mediating the response to stress and novelty, and in the establishment of LTD.
Asunto(s)
Adaptación Fisiológica/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Conducta Exploratoria/fisiología , Hipocampo/metabolismo , Plasticidad Neuronal/genética , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , Animales , Conducta Animal/fisiología , Corticosterona/metabolismo , Femenino , Regulación de la Expresión Génica/genética , Genes Inmediatos-Precoces/genética , Habituación Psicofisiológica/genética , Hipocampo/fisiopatología , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/metabolismo , Discapacidades para el Aprendizaje/fisiopatología , Potenciación a Largo Plazo/genética , Depresión Sináptica a Largo Plazo/genética , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. To define the molecular pathways involved in the response to stress further, we generated mice deficient (KO) in the calcium-stimulated adenylyl cyclase type VIII (AC8) by homologous recombination in embryonic stem cells. AC8 KO mice demonstrate a compromise in calcium-stimulated AC activity in the hippocampus, hypothalamus, thalamus, and brainstem. Hippocampal slices derived from AC8 KO mice fail to demonstrate CA1-region long-term depression after low-frequency stimulation, and AC8 KO mice also fail to activate CRE-binding protein in the CA1 region after restraint stress. To define the behavioral consequences of AC8 deficiency, we evaluated AC8 KO mice in the elevated plus-maze and open field. Although naive AC8 KO mice exhibit indices of anxiety comparable with that of wild-type mice, AC8 KO mice do not show normal increases in behavioral markers of anxiety when subjected to repeated stress such as repetitive testing in the plus-maze or restraint preceding plus-maze testing. These results demonstrate a novel role for AC8 in the modulation of anxiety.
Asunto(s)
Adenilil Ciclasas/genética , Ansiedad , Encéfalo/fisiología , Aprendizaje por Laberinto/fisiología , Estrés Psicológico/fisiopatología , Adenilil Ciclasas/deficiencia , Animales , Encéfalo/enzimología , Calcio/metabolismo , Quimera , Cruzamientos Genéticos , Potenciales Evocados , Femenino , Hipocampo/fisiología , Masculino , Ratones , Ratones Noqueados , Actividad Motora , Especificidad de Órganos , Fenotipo , Células Piramidales/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Olfato/fisiología , Estrés Psicológico/genéticaRESUMEN
To determine factors that contribute to the learning deficits observed in individuals with fetal alcohol syndrome, we examined the effects of early postnatal ethanol exposure on forms of synaptic plasticity thought to underlie memory. Treatment of rat pups with ethanol on postnatal day 7 impaired the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation and abolished homosynaptic long-term depression in the CA1 region of hippocampal slices prepared at postnatal day 30. An N-methyl-D-aspartate receptor-independent form of long-term potentiation induced by very high frequency stimulation could be induced in slices from ethanol-treated rats. Defects in long-term depression correlated with a diminished contribution of ifenprodil-sensitive N-methyl-D-aspartate receptors to synaptic transmission and defects in a spontaneous alternation behavioral task. Rats exposed to ethanol on postnatal day 7 also exhibited diminished sensitivity of synaptic N-methyl-D-aspartate receptors to block by ethanol at postnatal day 30 and decreased behavioral sedation to systemic ethanol injections. These results indicate that changes in synaptic plasticity and N-methyl-D-aspartate receptor function are likely to provide a neural substrate for the cognitive and behavioral changes that follow developmental ethanol exposure.
Asunto(s)
Animales Recién Nacidos/fisiología , Etanol/administración & dosificación , Plasticidad Neuronal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Conducta Animal/efectos de los fármacos , Esquema de Medicación , Resistencia a Medicamentos , Etanol/antagonistas & inhibidores , Etanol/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipnóticos y Sedantes/antagonistas & inhibidores , Inyecciones Subcutáneas , Aprendizaje/efectos de los fármacos , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Agents that block the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor induce a schizophrenialike psychosis in adult humans and injure or kill neurons in several corticolimbic regions of the adult rat brain. Susceptibility to the psychotomimetic effects of the NMDA antagonist, ketamine is minimal or absent in children and becomes maximal in early adulthood. We examined the sensitivity of rats at various ages to the neurotoxic effects of the powerful NMDA antagonist, MK-801. Vulnerability was found to be age dependent, having onset at approximately puberty (45 days of age) and becoming maximal in early adulthood. This age-dependency profile (onset of susceptibility in late adolescence) in the rat is similar to that for ketamine-induced psychosis or schizophrenia in humans. These findings suggest that NMDA receptor hypofunction, the mechanism underlying the neurotoxic and psychotomimetic actions of NMDA antagonists, may also play a role in schizophrenia.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Giro del Cíngulo/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/fisiopatología , Adolescente , Adulto , Factores de Edad , Animales , Corteza Cerebral/fisiopatología , Niño , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Giro del Cíngulo/fisiopatología , Humanos , Ketamina/farmacología , Sistema Límbico/fisiopatología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
Rats received bilateral injections of the excitotoxin, N-methyl-D,L aspartate, which resulted in degeneration of basal forebrain cholinergic (BFC) neurons in the nucleus basalis magnocellularis. Most tests of general neurological function revealed no differences between control rats and those with BFC lesions and where differences were found they appeared to be due to hyperemotionality. Rats with BFC lesions demonstrated significant deficits in working memory, as evaluated in an 8-arm radial maze. In addition, these rats showed a severe impairment in tactile discrimination learning, an effect of BFC lesions not previously demonstrated. We propose that cholinergic deafferentation of the somatosensory cortex with consequent disruption in somatosensory information processing might account at least in part for this effect.
Asunto(s)
Ganglios Basales/fisiología , Memoria/fisiología , Sustancia Innominada/fisiología , Tacto/fisiología , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/farmacología , Aprendizaje/fisiología , Masculino , N-Metilaspartato , Desempeño Psicomotor/fisiología , Ratas , Ratas Endogámicas , Sustancia Innominada/efectos de los fármacosRESUMEN
Excessive activation of N-methyl D-aspartate (NMDA) receptors by endogenous glutamate (Glu) causes excitotoxic neuronal degeneration in acute central nervous system injury syndromes such as stroke and trauma. Early attempts to link NMDA receptor hyperactivity (NRHyper) to Alzheimer disease (AD) were stymied by evidence in 3 separate species (mice, rats, and monkeys) that, with advancing age, the NMDA receptor system becomes markedly hypoactive. While this would seem to argue against a role for NMDA receptors in AD, we have recently found in animal studies that, when the NMDA receptor system is rendered markedly hypoactive, a disinhibition syndrome is triggered in which low-grade chronic excitotoxic activity (fueled by acetylcholine and Glu) is unleashed that can cause a widespread pattern of neuronal degeneration resembling that seen in AD. Therefore, we postulate that NMDA receptor hypoactivity (NRHypo) associated with advancing age may have an important contributory role in AD and that the main difference between the aging AD brain and the aging "normal" brain is that a heavier burden of certain adjunctive risk factors may be present in the AD brain that promote the NRHypo state and increase the likelihood that widespread neurodegeneration will occur.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Degeneración Nerviosa/fisiopatología , Neurotoxinas/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Animales , Humanos , Ilustración Médica , Sistema Nervioso Parasimpático/fisiopatología , Ratas , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
Procyclidine and ethopropazine, widely used as anti-parkinsonian agents because of their anti-cholinergic action, are also known to have NMDA antagonist properties. Unlike other NMDA antagonists, these agents-because of their anti-cholinergic action-are devoid of neurotoxic side effects. In the present study, we used a sciatic nerve ligation model that produces a hyperalgesic (neuropathic pain) state in adult rats to evaluate the ability of procyclidine or ethopropazine, either alone or in combination with an alpha(2) adrenergic agonist, to ameliorate neuropathic pain. We found that both procyclidine and ethopropazine alleviated thermal hyperalgesia in a dose dependent manner; when a marginally effective dose of these agents was combined with an ineffective dose of an alpha(2) adrenergic agonist (clonidine or guanabenz), the combination therapy provided effective and long-lasting relief from neuropathic pain. In addition, the combination therapy was free from neurotoxic or behavioral side effects, and hyperactivity, a side effect associated with procyclidine monotherapy, was counteracted by clonidine.
Asunto(s)
Antiparkinsonianos/farmacología , Hiperalgesia/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Fenotiazinas/uso terapéutico , Prociclidina/uso terapéutico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Agonistas alfa-Adrenérgicos/farmacología , Animales , Clonidina/farmacología , Constricción Patológica/complicaciones , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Guanabenzo/farmacología , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Ligadura , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Nervio CiáticoRESUMEN
Cholinergic neurons in the nucleus basalis region of the forebrain project to various portions of the cerebral cortex, including somatosensory cortex. Degeneration of these neurons and their cortical projections is a major feature of the neuropathology of Alzheimer's disease. Injecting an excitotoxin into the basal forebrain to destroy nucleus basalis neurons provides a potentially useful animal model for studying the role of these neurons in Alzheimer's disease. Previously, we demonstrated that rats with nucleus basalis excitotoxin lesions performed poorly on a tactile discrimination task and on a test of working memory. In an effort to clarify further the role of impaired memory versus other types of impairment (e.g. disrupted somatosensory processing due to cholinergic deafferentation of somatosensory cortex), we compared a group of rats with bilateral nucleus basalis excitotoxin lesions and a group with bilateral somatosensory cortical ablations on a variety of behavioral tasks. Rats with nucleus basalis lesions performed as well as controls on a battery of neurological tests but exhibited increased emotionality unlike rats with somatosensory cortical ablations which performed poorly on the battery but were not hyperemotional. The two lesion groups were impaired significantly and to a comparable degree in performing two-choice tactile discriminations in a T-maze. In contrast, only rats with nucleus basalis lesions showed deficits in working memory as tested in an eight-arm radial maze. Both lesion groups performed comparably to sham controls on a test of reference memory involving a black/white discrimination in a T-maze. The findings suggest that rats with nucleus basalis lesions manifest disturbances in several of the same spheres (emotionality, somatosensory information processing, memory) that are disrupted in Alzheimer's disease and further confirm the utility of the excitotoxin lesion approach for studying the pathophysiology of Alzheimer's disease.
Asunto(s)
Ganglios Basales/fisiología , Conducta Animal/fisiología , Fibras Colinérgicas/fisiología , Aprendizaje Discriminativo/fisiología , Memoria/fisiología , Corteza Somatosensorial/fisiología , Animales , Ácido Aspártico/análogos & derivados , Ganglios Basales/efectos de los fármacos , Emociones , Masculino , N-Metilaspartato , Degeneración Nerviosa , Ratas , Ratas EndogámicasRESUMEN
Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIbeta). Using homologous recombination, we created a mutant line of mice (delta1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in delta1-158 mice. Behavioral tests indicate that delta1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The delta1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.
Asunto(s)
Eliminación de Gen , Hipocampo/citología , Memoria/fisiología , Proteínas Asociadas a Microtúbulos/genética , Neuronas/fisiología , Estimulación Acústica , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Inhibidores de la Angiogénesis/farmacología , Animales , Conducta Animal , Western Blotting , Condicionamiento Psicológico , Señales (Psicología) , AMP Cíclico/farmacología , Estimulación Eléctrica/efectos adversos , Miedo , Femenino , Marcación de Gen , Heterocigoto , Homocigoto , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Actividad Motora , Neuronas/citología , Paclitaxel/farmacología , Fragmentos de Péptidos , Isótopos de Fósforo , Fosforilación , ARN Mensajero/biosíntesis , Tiempo de Reacción , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre , Tubulina (Proteína)/metabolismoRESUMEN
We review recent findings pertaining to several environmental agents (ethanol, phencyclidine, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane, and propofol) that have the potential to delete large numbers of neurons from the developing brain by a newly discovered mechanism involving interference in the action of neurotransmitters [glutamate and gamma-amino butyric acid (GABA) at (italic)N(/italic)-methyl-d-aspartate (NMDA)] and GABA(subscript)A(/subscript) receptors during the synaptogenesis period, also known as the brain growth-spurt period. Transient interference (lasting >= 4 hr) in the activity of these transmitters during the synaptogenesis period (the last trimester of pregnancy and the first several years after birth in humans) causes millions of developing neurons to commit suicide (die by apoptosis). Many of these agents are drugs of abuse (ethanol is a prime example) to which the human fetal brain may be exposed during the third trimester by drug-abusing mothers. Ethanol triggers massive apoptotic neurodegeneration in the developing brain by interfering with both the NMDA and GABA(subscript)A(/subscript) receptor systems, and this can explain the reduced brain mass and lifelong neurobehavioral disturbances associated with intrauterine exposure of the human fetus to ethanol (fetal alcohol syndrome). Exposure of the immature brain in a medical treatment context is also of concern because many of these agents are drugs used frequently as sedatives, tranquilizers, anticonvulsants, or anesthetics in pediatric and/or obstetrical medicine. Because this is a newly discovered mechanism, further research will be required to fully ascertain the nature and degree of risk posed by exposure of the developing human brain to environmental agents that act by this mechanism.
Asunto(s)
Apoptosis , Encéfalo/efectos de los fármacos , Encéfalo/embriología , Salud Ambiental , Xenobióticos/efectos adversos , Desarrollo Embrionario y Fetal , Femenino , Humanos , Neuronas/efectos de los fármacos , Neuronas/patología , Embarazo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Trastornos Relacionados con SustanciasRESUMEN
Pubescent (30 day old) male rats were maintained on an alcohol liquid diet containing 35% ethanol-derived calories (ALC) for 39 days or were pairfed an isocaloric control diet (PF). The concentration of alcohol in the diet was gradually increased to permit adaptation, then stabilized and then gradually tapered to prevent an alcohol withdrawal syndrome. Following a drug-free period (2 weeks), the males were mated with nontreated females. Offspring were evaluated on several developmental indices and on various learning/memory tasks to assess functional deficits in adulthood. Offspring sired by ALC-treated males did not differ from the offspring of PF males on several developmental parameters including body weights, when developmental landmarks appeared, or on tests of sensorimotor development. As adults, male offspring groups did not differ on tests of activity or on an object exploration/recognition task. However, male offspring of ALC-treated males demonstrated impaired acquisition performance (days and errors to criterion) on a win-shift spatial discrimination in an eight-arm radial maze and on a win-stay discrimination (days to criterion) conducted in a T-maze at a later age. The radial maze results were replicated in a subsequent experiment using different groups of rats.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Aprendizaje/efectos de los fármacos , Percepción Espacial/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cognición/efectos de los fármacos , Dieta , Aprendizaje Discriminativo/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Femenino , Masculino , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Equilibrio Postural/efectos de los fármacos , Embarazo , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Endogámicas , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrollo , Erupción Dental/efectos de los fármacosRESUMEN
Several experiments were conducted to study the effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on learning and memory in the rat. Rats displayed impaired performance on several sensorimotor tests and appeared grossly intoxicated when treated IP with 0.2 mg/kg MK-801, but not when treated with lower doses (0.05 or 0.1 mg/kg). Postacquisition performance on two spatial learning tasks involving working memory protocols (reinforced alternation and radial arm maze) was impaired by MK-801 at intoxicating doses (greater than or equal to 0.2 mg/kg) but not at lower doses (0.05 or 0.1 mg/kg). Using a position habit reversal task, we found that rats could learn to reverse a position habit while under the influence of a nonintoxicating dose of MK-801 (0.1 mg/kg), but when tested on the following day performed as if they did not recall what they had learned. Thus, acute administration of a nonintoxicating dose of MK-801 disrupts the retention of new information learned under the influence of the drug but does not interfere with the performance of tasks that are well learned before the drug is administered. Whether the performance deficits on the spatial learning tasks observed only following intoxicating doses of MK-801 reflect an effect on memory is not clear.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dibenzocicloheptenos/farmacología , Animales , Condicionamiento Operante/efectos de los fármacos , Maleato de Dizocilpina , Hábitos , Masculino , Memoria/efectos de los fármacos , Equilibrio Postural/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Endogámicas , Reflejo/efectos de los fármacosRESUMEN
In this article we review the hypothesis that impaired function of the N-methyl-Daspartate (NMDA) glutamate receptor system may be an important mechanism for understanding the pathophysiology of Alzheimer's disease (AD). We propose a two stage process, the first involving amyloidopathy, oxidative stress and/or energy metabolic disturbances promoting neuronal sensitivity to glutamate-induced excitotoxic injury to an extent that even normal amounts of Glu become excitotoxic. As a consequence, NMDA receptor-bearing neurons (and their NMDA receptors) are deleted from critical corticolimbic brain circuits, which leaves these circuits in an NMDA receptor hypofunctional (NRHypo) state. In the second stage this NRHypo state results in the disinhibition of a complicated neural circuitry that leads to widespread neurodegeneration in corticolimbic areas, consquent neurofibrillary tangle formation and cognitive decline. We propose that certain pharmacological methodes which have been found to protect against NRHypo-induced neurodegeneration in animal brain might be useful treatments for AD.
RESUMEN
N-Methyl-D-aspartate (NMDA) antagonists act by an anti-excitotoxic action to provide neuroprotection against acute brain injury, but these agents can also cause toxic effects. In low doses they induce reversible neuronal injury, but in higher doses they cause irreversible degeneration of cerebrocortical neurons. GABAmimetic drugs protect against the reversible neurotoxic changes in rat brain. Here we show that two GABAmimetic anesthetic agents--propofol and sodium thiopental--protect against the irreversible neurodegenerative reaction induced by the powerful NMDA antagonist, MK-801.
Asunto(s)
Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/farmacología , Giro del Cíngulo/efectos de los fármacos , Degeneración Nerviosa/inducido químicamente , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Anestésicos Intravenosos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Femenino , Ácido Glutámico/metabolismo , Giro del Cíngulo/patología , Giro del Cíngulo/fisiopatología , Necrosis , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Propofol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Tiopental/farmacología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The general anesthetics, nitrous oxide (N(2)O) and ketamine, are NMDA antagonists which, like other NMDA antagonists such as MK801, induce a neurotoxic reaction in the rat brain. For MK801 neurotoxicity, both age and sex are important variables (adult rats are more sensitive than immature rats and females are more sensitive than males). In this study we found that ketamine has this same age and sex dependency profile, and N(2)O has the same age but not sex dependency. Male and female rats are equally sensitive to N(2)O neurotoxicity.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Anestésicos Disociativos/farmacología , Corteza Cerebral/efectos de los fármacos , Ketamina/toxicidad , Neuronas/efectos de los fármacos , Neurotoxinas/toxicidad , Óxido Nitroso/toxicidad , Factores de Edad , Animales , Animales Recién Nacidos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/toxicidad , Femenino , Masculino , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Factores SexualesRESUMEN
The excitotoxin N-methyl aspartic acid was injected into the rat nucleus basalis to destroy basal forebrain cholinergic (BFC) neurons. In long-term survival experiments (up to 11 months post-lesion), conspicuous mineralized deposits were found in the globus pallidus and to a lesser extent in the thalamus. Deposits stained in a manner consistent with a composition of calcium and iron. Typically, deposits were absent from the center of the injection site, where BFC cell loss was most severe, but were present within the ventral and lateral globus pallidus where there was substantial sparing of BFC neurons. The similarity of this pathology to basal ganglia calcification and its relationship to Alzheimer's Disease and Down's syndrome is discussed.