RESUMO
This experiment determined if the loss of endogenous melatonin via pinealectomy affected rat CA1 and CA3 pyramidal neuron numbers over a 20-month span. Since pinealectomy eliminates many neurohormones, some rats received daily melatonin supplementation to determine if this would reverse its effects. CA1 pyramidal cells were significantly reduced between 2 and 4 months after pinealectomy. CA3 loss was evident at 2 months post-pinealectomy. Melatonin replacement in the drinking water prevented these effects and seemingly promoted the genesis of CA1 cells. Analyses of hippocampal thiobarbituric acid reactive substances (TBARS) levels at 3 and 20 months post-surgery, revealed no significant group differences in lipid peroxidation. However, hippocampal TBARS were higher at 20 than at 3 months in all groups. Pinealectomized rats exhibited a significantly higher ratio of reduced to oxidized glutathione at 3 months but not 20 months, when compared to the sham and melatonin-supplemented rats. This suggests that pinealectomy caused oxidative stress and a subsequent compensatory change in the glutathione system. These results indicate that endogenous melatonin is neuroprotective.
Assuntos
Glutationa/metabolismo , Peroxidação de Lipídeos/fisiologia , Melatonina/administração & dosagem , Glândula Pineal/metabolismo , Glândula Pineal/cirurgia , Células Piramidais/citologia , Células Piramidais/metabolismo , Administração Oral , Animais , Sobrevivência Celular/efeitos dos fármacos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Radicais Livres/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Acetylcholine and dopamine afferents reach their cortical targets during periods of synaptogenesis, and are in position to influence the cytoarchitectural development of cortical neurons. To determine the effect of removing these afferents on dendritic development, we lesioned rat pups at 7 days of age with the selective immunotoxins 192 IgG-saporin, or 6-hydroxydopamine, or both. One group of rats was killed in adulthood for neurochemistry and another was prepared for morphology using Golgi-Cox staining. Changes in morphology were compared in layer V pyramidal cells from medial prefrontal cortex, which sustained the greatest dopamine depletion, and in layer II/III pyramidal cells from retrosplenial cortex, which sustained the greatest choline acetyltransferase depletion. In rats with acetylcholine lesions, layer V medial prefrontal cells had smaller apical tufts and fewer basilar dendritic branches. Both apical and basilar spine density was substantially reduced. Layer II/III retrosplenial cells also had smaller apical tufts and substantially smaller basilar dendritic trees. Apical and basilar spine density did not change. In rats with dopamine lesions, layer V medial prefrontal cells had fewer oblique apical dendrites and atrophied basilar trees. Layer II/III retrosplenial cells had fewer apical dendritic branches. In neither area were spine densities significantly different from control. Neurons from rats with combined lesions were always smaller and less complex than those from singly lesioned rats. However, these cells were simple, additive composites of the morphology produced by single lesions. These data demonstrate that ascending acetylcholine and dopamine afferents play a vital role in the development of cortical cytoarchitecture.
Assuntos
Acetilcolina/fisiologia , Animais Recém-Nascidos/fisiologia , Córtex Cerebral/patologia , Dendritos/patologia , Dopamina/fisiologia , Animais , Anticorpos Monoclonais/toxicidade , Atrofia , Peso Corporal/fisiologia , Química Encefálica/fisiologia , Feminino , Saúde , Imunotoxinas/toxicidade , N-Glicosil Hidrolases , Neurônios Aferentes/efeitos dos fármacos , Neurotoxinas/toxicidade , Oxidopamina/toxicidade , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Células Piramidais/ultraestrutura , Ratos , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Simpatolíticos/toxicidadeRESUMO
Intraventricular injections of 192 IgG-saporin in the neonatal rat caused severe loss of basal forebrain cholinergic neurons and ectopic hippocampal ingrowths. These were evident at 24 months of age and thus, were lifelong consequences of the 192 IgG-saporin treatment. When tested as young adults on a novel water-escape radial arm maze, the rats with this lesion were slower to learn the task, committing significantly more working and reference memory errors before they achieved control level of performance. It is unlikely that this was a result of attentional impairment as the lesioned rats performed as vigilantly as controls in a five choice serial reaction time task. When tested in the Morris water maze at 22 months of age, they were slower at learning the hidden platform location. This contrasts with previous studies which have repeatedly shown that they normally acquire this task as young adults. It was concluded that this neonatal cholinergic lesion has modest but discernable effects on problem solving in young adulthood that are consistent with the reported effects of the lesion on cortical pyramidal neurons. The cognitive effects of the lesion may become more severe in aging, perhaps as a result of the added effects of aging on these neurons.
Assuntos
Acetilcolina/metabolismo , Comportamento Animal/fisiologia , Lesões Encefálicas/fisiopatologia , Neurônios/metabolismo , Prosencéfalo/patologia , Análise de Variância , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas/induzido quimicamente , Contagem de Células/métodos , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Imuno-Histoquímica/métodos , Imunotoxinas , Injeções Intraventriculares/métodos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , N-Glicosil Hidrolases , Prosencéfalo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptor de Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologiaRESUMO
Chronic brain hypoperfusion (CBH) using permanent occlusion of both common carotid arteries in an aging rat model, has been shown to mimic human mild cognitive impairment (MCI), an acknowledged high risk condition that often converts to Alzheimer's disease. An aging rat model was used to determine whether hippocampal nitric oxide (NO) is abnormally expressed following CBH for two or eight weeks. At each time point, spatial memory was measured with the Morris water maze and hippocampal A beta 1-40/1-42 concentrations were obtained using sandwich ELISA. Real-time amperometric measures of NO representing the constitutive isoforms of neuronal nitric oxide synthase (nNOS) and endothelial (e)NOS were also taken at each time point to ascertain whether NO levels changed as a result of CBH, and if so, whether such NO changes preceded or followed any memory or amyloid-beta pathology. We found that two weeks after CBH, NO hippocampal levels were upregulated nearly four-fold when compared to nonoccluded rats but no alteration in spatial memory of A beta products were observed at this time point. By contrast, NO concentration had declined to control levels by eight weeks but spatial memory was found significantly impaired and A beta 1-40 (but not A beta 1-42) had increased in the CBH group when compared to control rats. Since changes in shear stress are known to upregulate eNOS but generally not nNOS, these results suggest that shear stress induced by CBH hyperactivated vascular NO derived from eNOS in the first two weeks as a reaction by the capillary endothelium to maintain homeostasis of local cerebral blood flow. The return of vascular NO to basal levels after eight weeks of CBH may have triggered metabolic changes within hippocampal cells resulting in hippocampal dysfunction as reflected by spatial memory impairment and by accumulation of A beta 1-40 peptide. In conclusion, our study shows that CBH initiates spatial memory loss in aging rats thus mimicking human MCI and also increases A beta 1-40 in the hippocampus. The memory and amyloid changes are preceded by NO upregulation in the hippocampus. These preliminary findings may be important in understanding, at least in part, the molecular mechanisms that precede memory impairment during chronic brain ischemia and as such, the pre-clinical stage leading to Alzheimer's disease.
Assuntos
Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/metabolismo , Transtornos Cerebrovasculares/metabolismo , Hipocampo/metabolismo , Hipotensão/metabolismo , Transtornos da Memória/etiologia , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Circulação Cerebrovascular/fisiologia , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/fisiopatologia , Doença Crônica , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Hipotensão/complicações , Hipotensão/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Regulação para Cima/fisiologiaRESUMO
This experiment determined if pinealectomy (PX) affects the consequences of chronic, moderate brain ischemia. Rats were pinealectomized at 25 days of age and trained at 9 months on a tactile radial maze. They then underwent permanent occlusion of the common carotid arteries (2VO) or sham surgery, followed by maze retraining and then neurohistological assessment at 16 months. Combined PX + 2VO rats committed more working memory errors on the maze. 2VO itself caused a 10% reduction in hippocampal CA1 pyramidal cell number. PX alone caused a 21% reduction. Combined PX and 2VO caused the greatest reduction (32%) of CA1 cells. Similar results were seen for CA4. PX also increased glial fibrillary acidic protein immunoreactivity in both CA1 and CA4. Thus PX not only augmented the consequences of chronic brain ischemia but notably, PX itself caused hippocampal damage. These effects seemed not to result from the small cortical lesion caused by the PX procedure. The results are consistent with the hypothesis that endogenous melatonin is a neuroprotectant in the aging brain.
Assuntos
Comportamento Animal/fisiologia , Isquemia Encefálica/psicologia , Circulação Cerebrovascular/fisiologia , Glândula Pineal/fisiologia , Animais , Isquemia Encefálica/patologia , Estenose das Carótidas/patologia , Estenose das Carótidas/psicologia , Contagem de Células , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo/fisiologia , Pupila/fisiologia , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Tato/fisiologiaRESUMO
Adult rats who have undergone neonatal 192 IgG-saporin induced lesions of forebrain acetylcholine (ACH) neurons are normal on many behavioral tasks. In this study we determined whether ectopic hippocampal ingrowths, a documented consequence of these neonatal cholinergic lesions, functionally compensate for ACH denervation in these rats. Neonatal rats underwent systemic 6-hydroxydopamine (6-OHDA) injections on postnatal days (PND) 1-3 to prevent the ingrowths, and/or intraventricular 192 IgG-saporin injections on PND 7. The 192 IgG-saporin profoundly reduced basal forebrain p75 neurotrophin receptor (p75(NTR)) immunoreactive (IR) neurons. The 6-OHDA treatment abolished hippocampal and cortical dopamine-beta-hydroxylase (DBH) IR terminals, indicating the absence of normal norepinephrine (NE) innervation. Ectopic DBH IR and p75(NTR) IR varicosities which occurred in the hippocampus of 192 IgG-saporin treated rats were also eliminated by 6-OHDA treatment. Behavioral testing in adulthood indicated no effect of the treatments on the Morris water maze. 192 IgG-saporin treatment caused perseveration during delayed spatial alternation (DSA) and increased working but not reference memory errors on the radial arm maze (RAM). The 6-OHDA plus 192 IgG-saporin treated rats did not differ from the 192 IgG-saporin only rats on any task. These results indicate that ectopic hippocampal NE ingrowths do not functionally compensate for neonatal ACH lesions. Neonatal forebrain ACH lesion impairs working memory on the RAM but the absence of an effect on DSA contraindicates a basic dysfunction of short term memory. Despite severe combined neonatal loss of forebrain ACH and NE innervation, behavior is remarkably intact.
Assuntos
Acetilcolina/fisiologia , Hipocampo/fisiopatologia , Norepinefrina/fisiologia , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/farmacologia , Comportamento Animal/fisiologia , Contagem de Células , Colinérgicos/farmacologia , Denervação , Feminino , Hipocampo/química , Hipocampo/patologia , Imunotoxinas/farmacologia , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , N-Glicosil Hidrolases , Oxidopamina , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural/análise , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , SimpatolíticosRESUMO
In the present study, we sought to determine whether low-grade, chronic vascular insufficiency induced in a rodent model of chronic cerebrohypoperfusion is sufficient, in and of itself, to trigger cleavage of the amyloid precursor protein (APP) into beta A-sized fragments. We report that chronic two vessel occlusion (2VO) results in progressive accumulation of beta A peptides detected by Western analysis in aged rats correlating with a shift in the immunohistochemical localization of APP from neurons to extracellular deposits in brain parenchyma. These data indicate that the 2VO paradigm reproduces features of beta A biogenesis characteristic of sporadic Alzheimer's disease.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Isquemia Encefálica/metabolismo , Sequência de Aminoácidos , Animais , Western Blotting , Artéria Carótida Primitiva/fisiologia , Doença Crônica , Espaço Extracelular/metabolismo , Imuno-Histoquímica , Ligadura , Masculino , Dados de Sequência Molecular , Ratos , Ratos Sprague-DawleyRESUMO
Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients. Item scores from the Mattis Dementia Rating Scale (MDRS) and the Mini-Mental State Examination (MMSE) from 389 patients with probable Alzheimer's disease were submitted to principal component analysis with orthogonal rotation. The optimal solution identified four factors that reflected the cognitive domains of attention/registration, verbal fluency/reasoning, graphomotor/praxis and recent memory. A subgroup of patients was identified for whom both the MDRS and the MMSE had been administered within the 12 months before death. Scores were assigned to these patients for the four factors. These cognitive-domain scores were then correlated with postmortem choline acetyltransferase (ChAT) activity in the medial frontal cortex, inferior parietal cortex, and hippocampus. ChAT activity in both the medial frontal and the inferior parietal cortex significantly correlated with scores on the graphomotor/praxis factor. Medial frontal ChAT also correlated significantly with the attention/registration scores. Hippocampal ChAT correlated significantly only with recent memory scores. These results are consistent with current animal research regarding the effect of selective cholinergic lesions on behavior.
Assuntos
Doença de Alzheimer/fisiopatologia , Colina O-Acetiltransferase/metabolismo , Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Análise Fatorial , Feminino , Lobo Frontal/enzimologia , Lobo Frontal/patologia , Hipocampo/enzimologia , Hipocampo/patologia , Humanos , Masculino , Lobo Parietal/enzimologia , Lobo Parietal/patologia , Análise de RegressãoRESUMO
Adult rats underwent permanent bilateral occlusion of the common carotid arteries (2VO) to determine the effect of chronic cerebral ischemia on vision and retina. They were monitored post-surgically for the presence of the pupillary reflex to light. Some rats were tested for 6 months post-surgically on a radial arm maze task and then tested in another water-escape task which explicitly tested visual function. Another group of rats were tested post-surgically for 3 months on a task which simultaneously assessed visual and tactile discrimination ability. The thicknesses of the retinal sub-layers were then measured for some rats. Fourteen of the 25 rats that underwent 2VO lost the pupillary reflex. This seemed to occur within 5 days. Rats that lost the pupillary reflex but not rats whose reflex was intact, were impaired on all visually guided mazes. Tactile discrimination ability was unaffected. Only rats that lost the pupillary reflex showed reduced thickness of the retinal outer nuclear and plexiform layers, reduced cell density in the retinal ganglion cell layer and astrocytosis and degeneration of the optic tract. We conclude that 2VO can eliminate the pupillary reflex. Photoreceptors and retinal ganglion cells degenerate, but it is unclear if these are the cause(s) or result(s) of the loss of the pupillary reflex. These effects are accompanied by impairment of visually guided behavior. The possibility that visual system damage may also occur in acute ischemia merits further investigation.
Assuntos
Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/fisiologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Reflexo Pupilar/fisiologia , Retina/fisiopatologia , Doenças Retinianas/etiologia , Doenças Retinianas/fisiopatologia , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologia , Animais , Comportamento Animal/fisiologia , Artérias Carótidas/fisiopatologia , Modelos Animais de Doenças , Masculino , Nervo Óptico/irrigação sanguínea , Nervo Óptico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/fisiopatologiaRESUMO
The consequences of neonatal cholinergic lesions were examined in male and female rats. Rats were injected intraventricularly with 600 ng of 192 IgG-saporin at 7 days of age and examined behaviorally and histologically at 21, 45 and 90 days of age. 192 IgG-saporin profoundly reduced low affinity neurotrophin receptor (p75NTR)-immunoreactive (IR) and, to a lesser extent, choline acetyltransferase-IR cells in the basal forebrain. Presumptive sympathetic ingrowths (p75NTR- and dopamine beta-hydroxylase-IR) into the hippocampus were first apparent at 45 days of age and were not significantly greater at 90 days. Behaviorally, 192 IgG-saporin increased the time females, but not males, spent on the open arms of the elevated plus maze. Lesioned rats had longer platform location latencies in the Morris water maze only at the first hidden platform training session and did not differ on the rate of learning the platform location or on the no-platform probe trial. Generally, the effects of neonatal cholinergic lesions were not sex dependent and are unlikely to model Rett syndrome, a disorder characterized by forebrain cholinergic deficit which is seen almost exclusively in females.
Assuntos
Anticorpos Monoclonais/farmacologia , Colinérgicos/farmacologia , Imunotoxinas/farmacologia , Prosencéfalo/crescimento & desenvolvimento , Caracteres Sexuais , Acetilcolina/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Contagem de Células , Feminino , Hipocampo/química , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , N-Glicosil Hidrolases , Neurônios/química , Neurônios/citologia , Gravidez , Prosencéfalo/química , Prosencéfalo/citologia , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural/análise , Síndrome de Rett/fisiopatologia , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Sistema Nervoso Simpático/química , Sistema Nervoso Simpático/citologia , Sistema Nervoso Simpático/crescimento & desenvolvimentoRESUMO
Cross-generational chronic feeding of either a 5 or a 20% lyophilized Lake Huron (LH) or Lake Ontario (LO) chinook salmon diet to rats caused no observable effects on many behavioral dimensions including activity, exploration, sensorimotor function, and stereotypy. As assessed by the Morris water maze and the radial arm maze, there was no diet-induced impairment of spatial learning or long-term memory. There was no evidence that the fish diets caused an exaggerated response to food reward reduction as had been observed previously for rats fed Oswego area Lake Ontario salmon. Effects of the fish diets with the exception of one statistically significant but probably meaningless effect on the Morris water maze for females were found only for male rats and only for males who ate the 20% diet. F1 male rats were reluctant to traverse a runway for a single pellet reward. Performance of the reference/working memory version of the radial arm maze was affected for the F1 LO-20 rats and for the F2 LH-20 rats. Until further research is conducted it would be unwise to ignore indications that male rats may show some effect of chronic consumption of the highest concentration of these diets, particularly on tasks that require intact frontocortical dopamine function.
Assuntos
Ração Animal/toxicidade , Comportamento Animal/efeitos dos fármacos , Contaminação de Alimentos , Salmão , Análise de Variância , Animais , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recompensa , Fatores SexuaisRESUMO
This study, part of a larger project to determine the health consequences of both perinatal and adult exposure to contaminated salmon from the Great Lakes, determined the neurochemical effects of exposure of rats to chow adulterated with lyophilized salmon fillets. Concentrations of biogenic amines, their metabolites, and choline acetyltransferase (ChAT) were determined in the frontal cortex (FC), nucleus accumbens, caudate nucleus (CN), hippocampus (HC), and substantia nigra (SN) of adult rats who had been exposed, both perinatally and as adults, to standard rat chow adulterated with either 5 or 20% (w/w) lyophilized fillets from either Lake Huron (LH) or Lake Ontario (LO) salmon. Dopamine (DA) concentrations in the FC were significantly decreased following exposure to both 20% fish diets. CN DA concentrations were significantly reduced in rats exposed to all diets, while SN DA was decreased only in the LO20-fed animals. SN norepinephrine concentrations were reduced in all groups except for the LO5-fed rats. 3,4-Dihydroxyphenylacetic acid (DOPAC) concentrations in the FC were significantly increased in the LH20 and LO5 groups, while CN DOPAC concentrations were reduced in LH20, LO5, and LO20 animals. 5-Hydroxyindoleacetic acid concentrations were reduced in the FC and CN of all animals exposed to diets adulterated with Great Lakes salmon. ChAT concentrations were unaffected in rats exposed to any of the adulterated diets. The significant reductions in DA, particularly in the FC and CN, suggest that either fish-borne contaminants or consumption of fish, per se, may affect behaviors that require inhibition of normal responding. We conclude that consumption of contaminated fish from the Great Lakes may result in sufficient reductions in biogenic amine function to result in significant deficits in important behavioral functions in the rat and, by inference, in the perinatally exposed human.
Assuntos
Ração Animal/toxicidade , Monoaminas Biogênicas , Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Contaminação de Alimentos , Salmão , Poluentes Químicos da Água/efeitos adversos , Animais , Encéfalo/metabolismo , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Colina O-Acetiltransferase/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Chronic reductions in cerebral blood flow associated with aging and progressive neurodegenerative disorders can precipitate cognitive failure. To assess whether chronic cerebrovascular insufficiency elicits neuronal apoptosis, apoptotic cell death in the hippocampus was quantitated in a rat model of permanent carotid occlusion. Bilateral carotid artery occlusion (2VO) was shown to induce apoptotic morphology and DNA strand breaks in hippocampal neurons 2 and 27 weeks after ligation. The rate of pyramidal cell apoptosis was higher at chronic (27 weeks) compared to sub-chronic (2 weeks) time points. 2VO-induced apoptosis resulted in a decrease in total pyramidal cell number at 27 weeks but not at earlier time points, indicating progressive neuronal loss. Working and reference memory errors in the radial arm maze were strongly correlated with the number of apoptotic neurons in CA1 but not CA3 pyramidal cell fields. These data provide the first indication that apoptotic loss of pyramidal neurons may play a role in memory impairment associated with clinical conditions of chronic cerebrovascular insufficiency.
Assuntos
Arteriopatias Oclusivas/fisiopatologia , Doenças das Artérias Carótidas/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Neurônios/patologia , Animais , Apoptose/fisiologia , Arteriopatias Oclusivas/patologia , Arteriopatias Oclusivas/psicologia , Arteriopatias Oclusivas/cirurgia , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/psicologia , Doenças das Artérias Carótidas/cirurgia , Masculino , Células Piramidais/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Rats were subjected to bilateral carotid artery occlusion (2-VO) or sham occlusion (No-VO) and tested 12 weeks for visuo-spatial memory (VSM) function. After 14 weeks, 2-VO rats (N = 4) showing severe visuo-spatial memory impairment were given dimethyl sulfoxide (DMSO)-fructose 1,6-diphosphate (FDP) i.p. for seven days and retested on the water maze. After DMSO-FDP, a 54% improvement in their VSM was seen which nearly reached control No-VO values. Untreated 2-VO (N = 4) and No-VO (N = 8) rats showed no significant changes in their VSM. DMSO-FDP treatment was discontinued and rats were retested on the water maze but improvement was lost and VSM function regressed to pretreatment levels. Immunohistochemical examination showed minimal neuronal damage in all 2-VO rats and slight loss of microtubule associated protein-2. Glial fibrillary acidic protein immunostaining increase was observed only in untreated 2-VO rats. The results indicate that a DMSO-FDP combination improves VSM secondary to chronic brain hypoperfusion.
Assuntos
Envelhecimento/psicologia , Sequestradores de Radicais Livres/uso terapêutico , Glicólise/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Animais , Arteriopatias Oclusivas/complicações , Arteriopatias Oclusivas/tratamento farmacológico , Doença Crônica , Dimetil Sulfóxido/uso terapêutico , Quimioterapia Combinada , Frutosedifosfatos/uso terapêutico , Ataque Isquêmico Transitório/complicações , Masculino , Transtornos da Memória/etiologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Platelet activating factor (PAF), an endogenous proinflammatory agent, mediates neuronal survival, glutamate release, and transcriptional activation following excitotoxin challenge. To determine whether PAF receptor (PAFR) expression is altered during excitotoxicity, changes in PAFR mRNA localization were compared with markers of neuronal apoptosis and reactive gliosis following systemic injection of kainic acid. Data from semi-quantitative RT-PCR, in situ hybridization, DNA fragmentation, cellular morphology analysis, and immunohistochemistry demonstrate that the localization of PAFR mRNA is altered during kainic acid-induced neurodegeneration. While PAFR mRNA is normally exhibited by neurons and microglia in rat hippocampus, expression becomes restricted to apoptotic neurons and to glia involved in phagocytosing apoptotic debris following treatment with excitotoxin. PAFR mRNA is rarely detected in surviving neurons. These data provide the first indication that PAFR-expressing neurons may be preferentially susceptible to excitotoxic challenge.
Assuntos
Hipocampo/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Glicoproteínas da Membrana de Plaquetas/genética , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G , Estado Epiléptico/metabolismo , Transcrição Gênica , Animais , Apoptose , Astrócitos/patologia , Sobrevivência Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Gliose , Hipocampo/patologia , Ácido Caínico/toxicidade , Masculino , Neuroglia/patologia , Neurônios/patologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia , Transcrição Gênica/efeitos dos fármacosRESUMO
Manganese chloride (Mn) was dissolved in the drinking water (0, 2, or 10 mg/ml) of dams and their litters from conception until postnatal day (PND) 30. Parturition was uneventful in the Mn-exposed rats and no physical abnormalities were observed. The rats exposed to 10 mg/ml Mn showed a 2.5-fold increase in cortical Mn levels. Their weight gain was attenuated from PND 9-24 and they were hyperactive at PND 17. Neither the 2 nor the 10 mg/ml Mn-exposed groups differed from the controls on the elevated plus apparatus or on the Morris water maze and the radial arm maze. Brain monoamine levels and choline acetyltransferase activity were affected. Tyrosine hydroxylase immunohistochemistry showed that dopamine cells of the substantia nigra were intact. Glial fibrillary acidic protein immunoreactivity was not increased in cortex, caudate, and hippocampus. However, both the low- and high-dose Mn-exposed groups showing thinning of the cerebral cortex. This could have resulted from perinatal malnutrition or from a direct effect of Mn on cortical development.
Assuntos
Encéfalo/efeitos dos fármacos , Intoxicação por Manganês , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Análise de Variância , Animais , Animais Recém-Nascidos , Monoaminas Biogênicas/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/análise , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/análiseRESUMO
Seven day old rats received bilateral intraventricular injections (200 ng) of the immunotoxin 192 IgG-saporin. When assayed in adulthood, these rats showed an 84% loss of hippocampal and a 52% loss of cortical choline acetyltransferase (ChAT) activity. ChAT was unaffected in the caudate. Cholinergic neurons immunoreactive (IR) for the low affinity neurotrophin receptor (P75NTR) were severely reduced throughout the basal forebrain nuclei. Cortical and hippocampal norepinephrine were increased and these areas showed ingrowth of ectopic, P75NTR and dopamine beta-hydroxylase IR varicosities. These were probably sympathetic axons. No obvious forebrain dysmorphogenesis was observed and cortical thickness was unaffected. These rats showed no evidence of impaired spatial learning/memory as assessed by the Morris water maze and delayed spatial alternation. However, they were less active on the elevated plus apparatus and spent less time on the open arms, suggestive of increased timidity. 192 IgG-saporin appears to be a powerful tool to selectively lesion basal forebrain cholinergic neurons in the neonatal rat. Surprisingly, the neuromorphological and behavioral sequelae seem minimal. It may be necessary to achieve near-total neonatal destruction of forebrain cholinergic neurons before severe, lasting mnemonic effects are evident.
Assuntos
Acetilcolina/fisiologia , Anticorpos Monoclonais/toxicidade , Colinérgicos/toxicidade , Imunotoxinas/toxicidade , Neurônios/efeitos dos fármacos , Prosencéfalo/efeitos dos fármacos , Análise de Variância , Animais , Axônios/química , Feminino , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , N-Glicosil Hidrolases , Neurônios/ultraestrutura , Prosencéfalo/citologia , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural/análise , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Comportamento Espacial/efeitos dos fármacosRESUMO
Ten-month-old rats were subjected to permanent bilateral occlusion of both common carotid arteries (2-VO) to chronically but moderately reduce brain blood flow. 2-VO impaired Morris water maze acquisition as soon as 7 days post-surgery. 2-VO also caused a later-appearing impairment on the radial arm maze which did not reach significance until 63 days post-surgery. At 14 dats post-surgery there were no effects of 2-VO on hippocampal CA1 pyramidal cell number or density of glial fibrillary acidic protein (GFAP). Hippocampal choline acetyltransferase activity at 70 days was also unaffected by 2-VO. At 190 days post-surgery, however, the 2-VO rats showed loss of cells and increased GFAP density in CA1. The increased density of hippocampal GFAP correlated with radial arm maze but not Morris water maze impairment. It is suggested that 2-VO causes neuronal dysfunction which can be exacerbated by stress and thereby manifested on aversively motivated tasks such as the water maze. As well, CA1 neurons begin to degenerate after several weeks of the reduced energy availability caused by 2-VO and this impairs memory. Since reduced neuronal energy metabolism is associated with the progressive neurodegeneration that underlies disorders such as Alzheimer's, research should further explore the possibility that the effects of 2-VO may model age-related dementia.
Assuntos
Encéfalo/fisiologia , Circulação Cerebrovascular , Hipocampo/fisiologia , Aprendizagem em Labirinto , Memória/fisiologia , Células Piramidais/citologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Artéria Carótida Primitiva/fisiologia , Colina O-Acetiltransferase/metabolismo , Proteína Glial Fibrilar Ácida/análise , Hipocampo/irrigação sanguínea , Hipocampo/patologia , Masculino , Análise Multivariada , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Valores de Referência , Fluxo Sanguíneo Regional , Fatores de TempoRESUMO
Two- to 3-day-old rat pups received bilateral intracerebroventricular (i.c.v.) injections of 2.0 nmol/microliters AF64A or vehicle. Half of the pups had been preinjected i.c.v. with hemicholinium-3 (HC3) and the other half with saline. The administration of AF64A impaired spatial learning/memory and caused brain damage characterized by marked loss of forebrain cortical/subcortical tissue and ventricular hypertrophy when these were assessed in adulthood. Neither the behavioral nor the histopathological effects of AF64A were observed in rats that had been pretreated with HC3. Since HC3 is a potent and relatively selective inhibitor of high affinity choline uptake (HACU), the results indicate that the toxic effects of AF64A in the neonatal rat are dependent upon its uptake via the HACU site. If as other research suggests, this site is primarily on Ach neurons in the neonatal rat, then the consequences of neonatal damage to cholinergic neurons are severe for forebrain development.