RESUMO
Oxytocin and vasopressin secretion from the posterior pituitary gland are required for normal pregnancy and lactation. Oxytocin secretion is relatively low and constant under basal conditions but becomes pulsatile during birth and lactation to stimulate episodic contraction of the uterus for delivery of the fetus and milk ejection during suckling. Vasopressin secretion is maintained in pregnancy and lactation despite reduced osmolality (the principal stimulus for vasopressin secretion) to increase water retention to cope with the cardiovascular demands of pregnancy and lactation. Oxytocin and vasopressin secretion are determined by the action potential (spike) firing of magnocellular neurosecretory neurons of the hypothalamic supraoptic and paraventricular nuclei. In addition to synaptic input activity, spike firing depends on intrinsic excitability conferred by the suite of channels expressed by the neurons. Therefore, we analysed oxytocin and vasopressin neuron activity in anaesthetised non-pregnant, late-pregnant, and lactating rats to test the hypothesis that intrinsic excitability of oxytocin and vasopressin neurons is increased in late pregnancy and lactation to promote oxytocin and vasopressin secretion required for successful pregnancy and lactation. Hazard analysis of spike firing revealed a higher incidence of post-spike hyperexcitability immediately following each spike in oxytocin neurons, but not in vasopressin neurons, in late pregnancy and lactation, which is expected to facilitate high frequency firing during bursts. Despite lower osmolality in late-pregnant and lactating rats, vasopressin neuron activity was not different between non-pregnant, late-pregnant, and lactating rats, and blockade of osmosensitive ΔN-TRPV1 channels inhibited vasopressin neurons to a similar extent in non-pregnant, late-pregnant, and lactating rats. Furthermore, supraoptic nucleus ΔN-TRPV1 mRNA expression was not different between non-pregnant and late-pregnant rats, suggesting that sustained activity of ΔN-TRPV1 channels might maintain vasopressin neuron activity to increase water retention during pregnancy and lactation.
Assuntos
Núcleo Basal de Meynert/metabolismo , Ocitocina/metabolismo , Vasopressinas/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Núcleo Basal de Meynert/patologia , Feminino , Hipotálamo/metabolismo , Lactação/metabolismo , Lactação/fisiologia , Ejeção Láctea/efeitos dos fármacos , Neurônios/metabolismo , Ocitocina/farmacologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Gravidez , Ratos , Núcleo Supraóptico/metabolismo , Vasopressinas/farmacologiaRESUMO
The present study was aimed to investigate the pre-treatment effect of Centella asiatica (CeA) extract on long-term potentiation (LTP) in a rat model of Alzheimer's disease (AD). A total of 32 male Wistar rats weighing 380 ± 30 g were randomly divided into four groups (n = 8). Group 1 (C: Control): the control group. Group 2 (L: Lesion): The nucleus basalis of Meynert (NBM) of rats' brain was bilaterally destroyed by injection of Ibotenic acid. Group 3 (CeA): Animals in this group received the CeA leaf extract for only a period of six weeks. Group 4 (CeA + L): The NBM of rats was destroyed by Ibotenic acid after six weeks of a diet containing the CeA leaf extract. In all groups, LTP was recorded using the electrophysiological technique and fEPSP after high frequency stimulation (HFS). The results showed that the slope and amplitude of PS as well as the sub-curve level significantly increased in the CeA + L group compared with the L and CeA groups. The CeA extract improved and strengthened the slope, amplitude and sub-curve surface of cumulative waves in animals with NBM lesion. The results showed that administration CeA extract for six weeks before induction of NBM lesion and induction of Alzheimer could enhance memory. In other words, the CeA extract had a preventive or protective role. The present study showed that CeA had a protective role for neurons among rats with NBM lesion.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Plantas Medicinais , Doença de Alzheimer/patologia , Animais , Núcleo Basal de Meynert/patologia , Modelos Animais de Doenças , Ácido Ibotênico/farmacologia , Masculino , Memória/efeitos dos fármacos , Neurônios/patologia , Ratos WistarRESUMO
The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse-3 (GSK-3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK-3 by lateral ventricular infusion of wortmannin (WT) and GF-109203X (GFX), the inhibitors of phosphoinositol-3 kinase (PI3-K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor-κB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK-3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK-3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.
Assuntos
Acetilcolina/metabolismo , Núcleo Basal de Meynert/metabolismo , Lobo Frontal/metabolismo , Quinase 3 da Glicogênio Sintase/genética , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Androstadienos/farmacologia , Animais , Transporte Axonal/efeitos dos fármacos , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/patologia , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/patologia , Regulação da Expressão Gênica , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/genética , Indóis/farmacologia , Cloreto de Lítio/farmacologia , Masculino , Maleimidas/farmacologia , NF-kappa B/genética , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Técnicas Estereotáxicas , Wortmanina , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Ovariectomy is known as "surgical menopause" with decreased levels of estrogen in female rodents. Its reported risks and adverse effects include cognitive impairment. The action of hydroponic Teucrium polium on nucleus basalis of Meynert (bnM) neurons following 6 weeks of ovariectomy was carried out. The analysis of spike activity was observed by on-line selection and the use of a software package. Early and late tetanic, - posttetanic potentiation and depression of neurons to high frequency stimulation of hippocampus were studied. The complex averaged peri-event time and frequency histograms were constructed. The histochemical study of the activity of Са(2+)-dependent acid phosphatase was observed. In conditions of hydroponic Teucrium polium administration, positive changes in neurons and gain of metabolism leading to cellular survival were revealed. The administration of Teucrium polium elicited neurodegenerative changes in bnM.
Assuntos
Núcleo Basal de Meynert/efeitos dos fármacos , Hidroponia , Fármacos Neuroprotetores/farmacologia , Ovariectomia/efeitos adversos , Extratos Vegetais/farmacologia , Teucrium , Animais , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patologia , Feminino , Hidroponia/métodos , Fármacos Neuroprotetores/isolamento & purificação , Ovariectomia/tendências , Extratos Vegetais/isolamento & purificação , RatosRESUMO
Alzheimer's disease (AD) is a common neurodegenerative condition that affects the elderly population. Its primary symptom is memory loss. The memory dysfunction in AD has been associated with cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert (NBM). Zizyphus jujube (ZJ) activates choline acetyltransferase and may have beneficial effects in AD patients. This study investigates the effect of ZJ extract in intact rats and in rat model of AD. 49 male Wistar rats were divided into seven equal groups (1-control, without surgery, received water), 2-AD (bilateral NBM lesion, received water), 3 and 4-AD + ZJ (NBM bilateral lesion, received ZJ extract 500 and 1,000 mg/kg b.w. per day for 15 days), 5-sham (surgery: electrode introduced into NBM without lesion, received water), 6 and 7-without surgery and lesion, received ZJ extract-the same as groups 3 and 4). The learning and memory performance were assessed using passive avoidance paradigm, and the memory cognition for spatial learning and memory was evaluated by Morris water maze. In shuttle box test ZJ extract (500 and 1,000 mg) significantly increased step-through latency in AD + ZJ groups compared with AD group. In Morris water maze test (in probe day), both AD + ZJ groups receiving extract (500 and 1,000 mg) demonstrated significant preference for the quadrant in which the platform was located on the preceding day as compared with AD group. Our results suggested that ZJ has repairing effects on memory and behavioral disorders produced by NBM lesion in rats and may have beneficial effects in treatment of AD patients.
Assuntos
Núcleo Basal de Meynert/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Deficiências da Aprendizagem/prevenção & controle , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ziziphus/química , Animais , Núcleo Basal de Meynert/patologia , Comportamento Animal/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Ratos , Ratos WistarRESUMO
In the present study the lamellar complex (LC, Golgi complex) changes in the major cholinergic nuclei of the human basal forebrain - the nucleus basalis of Meynert (NBM), the vertical nucleus of the diagonal band of Broca (VDB) and hypothalamus--the tuberomamillary (TMN), the medial mammillary (MMN) and supraoptic (SON) nuclei were analyzed considering the WHO aging classification. The increase in the size of the LC was present in NBM, MMN and SON in the 3rd age group of elderly people (60-74 years of age), in the VDB--in the 4th group (75-89 years of age), whereas in the TMN LC changes were not apparent. In conclusion, the WHO aging classification reflects the LC values age ranges and can be used to estimate age-related alterations of this parameter. The increase in the size of the neuronal LC in elderly people may represent the compensatory reaction of neuroplasticity triggered by the aging process.
Assuntos
Envelhecimento/patologia , Prosencéfalo Basal/patologia , Núcleo Basal de Meynert/patologia , Feixe Diagonal de Broca/patologia , Complexo de Golgi/patologia , Hipotálamo/patologia , Neurônios/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Prosencéfalo Basal/metabolismo , Núcleo Basal de Meynert/metabolismo , Feixe Diagonal de Broca/metabolismo , Complexo de Golgi/metabolismo , Humanos , Hipotálamo/metabolismo , Pessoa de Meia-Idade , Neurônios/metabolismo , Receptores Colinérgicos/metabolismoRESUMO
OBJECTIVE: The melanocortin 4 receptor (MC4R) is an essential regulator of energy homeostasis and metabolism, and MC4R mutations represent the most prevalent monogenetic cause of obesity in humans known to date. Hypothalamic MC4Rs in rodents are well characterized in neuroanatomical and functional terms, but their expression pattern in the human hypothalamus is unknown. DESIGN AND METHODS: To determine the topographic distribution and identity of cells expressing MC4R mRNA in the human hypothalamus, locked nucleic acid in situ hybridization was performed on nine human postmortem hypothalami. In addition, co-expression of MC4R with glial fibrillary acidic protein (GFAP), vasopressin/oxytocin (AVP/OXT), corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), agouti-related protein (AgRP), and α-melanocyte stimulating hormone (α-MSH) was examined. RESULTS: Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed AVP/OXT. Co-expression with AVP/OXT in the PVN was less abundant. We did not observe co-expression of MC4R mRNA and GFAP, CRH, NPY, AgRP, or α-MSH. However, fiber-like staining of NPY, AgRP, and α-MSH was found adjacent to MC4R-positive cells in the PVN. CONCLUSION: Expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners AgRP and α-MSH.
Assuntos
Regulação da Expressão Gênica , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína Relacionada com Agouti/metabolismo , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patologia , Feminino , Humanos , Hipotálamo/patologia , Imuno-Histoquímica , Hibridização In Situ , Ligantes , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Especificidade de Órgãos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , RNA Mensageiro/metabolismo , Receptor Tipo 4 de Melanocortina/genética , Núcleo Supraóptico/metabolismo , Núcleo Supraóptico/patologia , alfa-MSH/genéticaRESUMO
The intranasal administration of glutamate antibodies in the dose of 300 microg/kg one hour after damage on the level of mRNA expression of Dffb gene which codes caspase-activated DNase which participates in intranucleosome fragmentation of genome DNA in apoptosis was investigated in experimental Alzheimer's disease induced by injection of neurotoxic fragment of beta-amyloid protein Abeta25-35 in Meynert basal magnocellular nuclei on rats. On the Day 3 after Abeta25-35 injection is observed significant decrease of the level of mRNA expression of Dffb gene in prefrontal cortex in 37%, and in hippocampus in 62% in the experiment group versus the control group. These differences were not found in the hypothalamus when comparing the experimental and control animals. It was suggested that repressive effect of glutamate antibodies on the level of mRNA expression of Dffb gene reflects stabilization of processes taking place in brain cells in experimental Alzheimer's disease, and in its turn the intensiveness of nerve and glial cells apoptotic death is decreased.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Anticorpos/uso terapêutico , Córtex Cerebral/efeitos dos fármacos , Desoxirribonucleases/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , RNA Mensageiro/antagonistas & inibidores , Administração Intranasal , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Animais , Anticorpos/imunologia , Apoptose/efeitos dos fármacos , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/patologia , Córtex Cerebral/metabolismo , Desoxirribonucleases/genética , Desoxirribonucleases/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/imunologia , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Masculino , Proteínas de Ligação a Poli-ADP-Ribose , RNA Mensageiro/biossíntese , Ratos , Ratos WistarRESUMO
BACKGROUND AND PURPOSE: Previous evidence from MRI and acetylcholinesterase histochemistry suggests cholinergic fibers are affected in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: As a measure of cholinergic function, we assessed choline acetyltransferase (ChAT) activities in the frontal and temporal neocortices and the immunocytochemical distribution of ChAT and p75 neurotrophin receptor (P75(NTR)) by in vitro imaging in the nucleus basalis of Meynert of CADASIL subjects. RESULTS: ChAT activities were significantly reduced by 60% to 70% in frontal and temporal cortices of CADASIL cases, as were ChAT and P75(NTR) immunoreactivities in the nucleus basalis. CONCLUSIONS: Our findings suggest cholinergic neuronal impairment in CADASIL and implicate cholinomimetic therapy for subcortical vascular dementias.
Assuntos
Núcleo Basal de Meynert/metabolismo , CADASIL/metabolismo , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/metabolismo , Lobo Frontal/metabolismo , Vias Neurais/metabolismo , Lobo Temporal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Núcleo Basal de Meynert/patologia , CADASIL/patologia , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Fibras Colinérgicas/patologia , Regulação para Baixo/fisiologia , Feminino , Lobo Frontal/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Receptor de Fator de Crescimento Neural/metabolismo , Lobo Temporal/patologiaRESUMO
OBJECTIVE: To observe the protective effect of Panax notoginseng saponins (PNS) on the level of synaptophysin ptotein in brain in rat model with Alzheimer's disease (AD). METHOD: The AD rat models were established by intra-peritoneal injection of D-galactose combined with excitatory neurotoxin ibotenic acid injection into bilateral nbM. The activity and content of synaptophysin protein in brain were determined by immunohistochemistry analysis. RESULT: PNS could reduce the lesion of level of synaptophysin protein in brain, as compared with those of model group's rats. CONCLUSION: PNS plays a protective role by reducing down of the level of synaptophysin protein in brain in lesion of AD animal model.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Ginsenosídeos/farmacologia , Panax , Sinaptofisina/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/patologia , Encéfalo/patologia , Galactose/toxicidade , Ginsenosídeos/isolamento & purificação , Ácido Ibotênico/toxicidade , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Panax/química , Plantas Medicinais/química , Ratos , Ratos WistarRESUMO
Transgenic mice carrying the human mutated SOD1 gene with a glycine/alanine substitution at codon 93 (G93A) are a widely used model for the fatal human disease amyotrophic lateral sclerosis (ALS). In these transgenic mice, we carried out a neurochemical study not only restricted to the primarily affected regions, the cervical and lumbar segments of the spinal cord, but also to several other brain regions. At symptomatic (110 and 125 days of age), but not at pre-symptomatic (55 days of age) stages, we found significant decreases in catalytic activity of the cholinergic enzyme, choline acetyltransferase (ChAT) in the hippocampus, olfactory cortex and fronto-parietal cortex. In parallel, we observed a decreased number of basal forebrain cholinergic neurons projecting to these areas. No alterations of the cholinergic markers were noticed in the striatum and the cerebellum. A widespread marker for GABAergic neurons, glutamate decarboxylase (GAD), was unaffected in all the areas examined. Alteration of cholinergic markers in forebrain areas was paralleled by concomitant alterations in the spinal cord and brainstem, as a consequence of progressive apoptotic elimination of cholinergic motor neuron. Gestational supplementation of choline, while able to result in long-term enhancement of cholinergic activity, did not improve transgenic mice lifespan nor counteracted cholinergic impairment in brain regions and spinal cord.
Assuntos
Acetilcolina/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Núcleo Basal de Meynert/metabolismo , Fibras Colinérgicas/metabolismo , Regulação para Baixo/fisiologia , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Núcleo Basal de Meynert/patologia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Colina/metabolismo , Colina/uso terapêutico , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Vias Neurais/metabolismo , Vias Neurais/patologia , Gravidez , Medula Espinal/metabolismo , Medula Espinal/patologia , Superóxido Dismutase-1 , Resultado do Tratamento , Ácido gama-Aminobutírico/metabolismoRESUMO
BACKGROUND: The neurodegenerative process in Alzheimer's disease (AD) and in the Lewy body variant of AD (LBV) patients is characterized by cholinergic dysfunction and deposition of amyloid beta-peptide (Abeta) 1-40 and 1-42; however, the differential effects of Abeta species on the cholinergic system are not completely clear. OBJECTIVE: To better understand the relationship between levels of Abeta1-40 and 1-42 on cholinergic deficits in AD and LBV patients. METHODS: Levels of choline acetyltransferase (ChAT) activity and ChAT immunoreactivity in the plaques in the frontal cortex of patients with AD and LBV were correlated with Abeta1-42 and 1-40 levels determined by ELISA and with neuropathologic and neurologic markers. RESULTS: Although the overall levels of ChAT activity were reduced in AD and LBV cases, there was a direct correlation with Abeta1-42 levels. Furthermore, patients with high Abeta1-42 levels had more abundant cholinergic dystrophic neurites in the plaques than cases with lower Abeta1-42. CONCLUSION: Abeta1-42 may also trigger cholinergic dysfunction by promoting aberrant neuritic sprouting.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/fisiologia , Fibras Colinérgicas/patologia , Lobo Frontal/patologia , Doença por Corpos de Lewy/patologia , Fragmentos de Peptídeos/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/análise , Núcleo Basal de Meynert/patologia , Colina O-Acetiltransferase/análise , Feminino , Lobo Frontal/química , Proteína GAP-43/análise , Humanos , Doença por Corpos de Lewy/metabolismo , Masculino , Proteínas do Tecido Nervoso/análise , Neuritos/ultraestrutura , Emaranhados Neurofibrilares , Testes Neuropsicológicos , Fragmentos de Peptídeos/análise , Placa Amiloide/química , Método Simples-CegoRESUMO
Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/patologia , Fibras Colinérgicas/patologia , Acetilcolinesterase/metabolismo , Envelhecimento/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Amiloide/análise , Precursor de Proteína beta-Amiloide/genética , Amiloidose/fisiopatologia , Animais , Núcleo Basal de Meynert/patologia , Contagem de Células , Tamanho Celular , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Lobo Frontal/enzimologia , Lobo Frontal/patologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Neocórtex/química , Neocórtex/patologia , Neurônios/enzimologia , Neurônios/patologia , Prosencéfalo/enzimologia , Prosencéfalo/patologiaRESUMO
It has been reported that the ACTH-(4-9) analog H-Met(O(2))-Glu-His-Phe-D-Lys-Phe-OH (ORG 2766) administered in adulthood has trophic effects on neuronal tissue and when given postnatally, it can induce long-lasting changes in brain development. In the present study, we investigated whether early postnatal treatment with ORG 2766 affects adult neuronal vulnerability, i.e. the sensitivity of cholinergic neurons against excitotoxic damage. Wistar rat pups received injections of ORG 2766 or saline on postnatal days 1, 3 and 5 and were then left undisturbed until adulthood. At the age of 6 months, the animals were subjected to unilateral lesion of magnocellular basal nucleus by infusion of high dose of N-methyl-D-aspartate (NMDA). The effects of the excitotoxic insult were studied 28 hours and 12 days after the lesion by measuring both the acute cholinergic and glial responses, and the final outcome of the degeneration process. Twenty eight hours after NMDA infusion, postnatally ACTH-(4-9)-treated animals showed stronger suppression of choline-acetyltransferase immunoreactivity and increased reaction of glial fibrillary acidic protein -immunopositive astrocytes in the lesioned nucleus compared to control animals. However, 12 days post-surgery, the NMDA-induced loss of cholinergic neurons, as well as the decrease of their acetylcholinesterase -positive fibre projections in the cortex, were less in ACTH-(4-9) animals. Our data indicate that the early developmental effects of ACTH-(4-9) influence intrinsic neuroprotective mechanisms and reactivity of neuronal and glial cells, thereby resulting in a facilitated rescuing mechanism following excitotoxic injury.
Assuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Hormônio Adrenocorticotrópico/farmacologia , Animais Recém-Nascidos/fisiologia , Núcleo Basal de Meynert/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , N-Metilaspartato/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Núcleo Basal de Meynert/enzimologia , Núcleo Basal de Meynert/patologia , Contagem de Células , Colina O-Acetiltransferase/metabolismo , Agonistas de Aminoácidos Excitatórios/toxicidade , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , N-Metilaspartato/toxicidade , Ratos , Ratos WistarRESUMO
Gacyclidine, a novel, noncompetitive NMDA receptor antagonist, was injected (i.v.) into rats at three different doses to determine if the drug could promote behavioral recovery and reduce the behavioral and anatomical impairments that occur after bilateral contusions of the medial frontal cortex (MFC). In the Morris water maze, contused rats treated with gacyclidine at a dosage of 0.1 mg/kg performed better than their vehicle-treated conspecifics. Rats given gacyclidine at either 0.3 or 0.03 mg/kg performed better than brain-injured controls, but not as well as those treated with 0.1 mg/kg. Counts of surviving neurons in the nucleus basalis magnocellularis (NBM) and the medial dorsal nucleus (MDN) of the thalamus were used to determine whether gacyclidine treatment attenuated secondary cell death. In both the NBM and the MDN, the counts revealed fewer surviving neurons in untreated contused rats than in gacyclidine-treated rats. Increases in the size and number of microglia and astrocytes were observed in the striatum of gacyclidine-treated contused brains. Although most consequences of MFC contusions were attenuated, we still observed increases in ventricle dilation and thinning of the cortex. In fact, the ventricles of rats treated with 0.1 mg/kg of gacyclidine were larger than those of their vehicle treated counterparts, although we observed no behavioral impairment.