RESUMO
We investigated the effects of egg phosphatidylcholine (PC) combined with vitamin B12 on memory in the Morris water maze task, and on choline and acetylcholine (ACh) concentrations in the brain of rats. Animals with nucleus basalis Magnocellularis (NBM) lesion received intragastric administration of egg PC or vitamin B12, or both for 18 days. Memory acquisition and retention were remarkably impaired in NBM lesioned rats compared with in sham-operated control. NBM lesioned group had lower choline and ACh concentrations than control group in the frontal cortex. High dose of egg PC alone significantly increased choline concentration, but did not change ACh concentration in the frontal cortex. High dose of vitamin B12 alone did not change choline and ACh concentrations in the brain. Either egg PC or vitamin B12 did not improve memory acquisition and retention. However, low dose of egg PC combined with vitamin B12 significantly increased ACh concentration and improved memory acquisition and retention in the NBM lesioned rats. We concluded that egg PC combined with vitamin B12 improved the memory impairment of NBM lesioned rats through the action on the cholinergic neurons.
Assuntos
Transtornos da Memória/tratamento farmacológico , Fosfatidilcolinas/uso terapêutico , Substância Inominada/patologia , Vitamina B 12/uso terapêutico , Acetilcolina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Colina/metabolismo , Ovos , Masculino , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/farmacologia , Ratos , Ratos Wistar , Substância Inominada/metabolismo , Vitamina B 12/administração & dosagem , Vitamina B 12/farmacologiaRESUMO
The present investigation considered the effects of cochlear damage caused by exposure to intense sound on the nucleus magnocellularis of the chick. Neonatal chicks exposed to intense sound were separated into four groups with post-exposure recovery durations of 0, 15, 27, and 43 days. Four age-matched, non-exposed control groups were also formed. At each recovery interval, the control and exposed birds were sacrificed and their brains prepared for paraffin embedding. The brain stem region containing the nucleus magnocellularis (NM) was serially sectioned in the coronal plane. All sections containing NM cells were identified and then coded in terms of their percentile distance from the most caudolateral section. Sections along the nucleus at the 15th, 30th, 50th, 65th, 80th, and 95th percentile positions were selected for evaluation, and the cross-sectional areas of individual NM cells in these sections were then measured. Cell areas were corrected for the bias introduced by eccentricity of the nucleus. The number of NM cells per 1,000 microm2 was also calculated at the 50th and 65th percentile positions. These procedures were repeated for the age-matched, non-exposed control animals. The cross-sectional cell area in exposed animals, immediately after the exposure, was reduced significantly at all positions, but returned to near normal by 43 days of recovery. However, the coronal area of NM in the sections at the 50th and 65th percentile position, as well as NM cell density, were unaffected by the exposure at all recovery intervals. The observation of structural recovery in NM cells at 43 days post-exposure was remarkable because it occurred at least 4 weeks after complete functional restoration of single-cell activity in the NM. The shrinkage in NM cell size throughout the nucleus may be due to a general reduction in spontaneous activity in the cochlear nerve fibers caused by the acoustic injury to the chick basilar papilla.
Assuntos
Galinhas/anatomia & histologia , Cóclea/patologia , Substância Inominada/patologia , Estimulação Acústica , Animais , Contagem de Células , Tamanho CelularRESUMO
We have identified a class of small organic molecules, derived from the indolocarbazole K-252a, that promote the survival of cultured neurons. However, many of these indolocarbazoles inhibit protein kinase C and neurotrophin-activated tyrosine kinase receptors. These kinase inhibitory activities may limit the utility of these compounds for neurological disorders. A bis-ethyl-thiomethyl analogue of K-252a, CEP-1347/KT-7515, has been identified that lacks protein kinase C and tyrosine kinase receptor inhibitory activities, yet retains the ability to promote survival of cultured neurons, including cholinergic neurons derived from the basal forebrain. In the present studies, CEP-1347/KT-7515 was assessed for neurotrophic activity on basal forebrain neurons of in vivo rats following excitotoxic insult. Ibotenate infusion into the nucleus basalis magnocellularis reduced levels of choline acetyltransferase activity in the cortex, as well as reduced numbers of choline acetyltransferase-immunoreactive and retrogradely (FluoroGold)-labelled cortically-projecting neurons in the nucleus basalis. Systemically administered CEP-1347/KT-7515 attenuated the loss of cortical choline acetyltransferase activity and the loss of the number of choline acetyltransferase-immunoreactive and retrogradely-labelled FluoroGold neurons in the nucleus basalis. Moreover, CEP-1347/KT-7515 ameliorated the loss of cortical choline acetyltransferase if administration was initiated one day, but not seven days post-lesion. Together, these results demonstrate that CEP-1347/KT-7515 protects damaged cortically-projecting basal forebrain neurons from degeneration. Thus, CEP-1347/KT-7515 may have therapeutic potential in neurodegenerative diseases, such as Alzheimer's disease, in which basal forebrain cholinergic neurons degenerate.
Assuntos
Carbazóis/farmacologia , Colina O-Acetiltransferase/metabolismo , Indóis/farmacologia , Neurônios/fisiologia , Estilbamidinas , Substância Inominada/fisiologia , Animais , Transporte Axonal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/enzimologia , Lobo Frontal/fisiologia , Lateralidade Funcional , Ácido Ibotênico/toxicidade , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Substância Inominada/efeitos dos fármacos , Substância Inominada/patologiaRESUMO
Peripheral injection of the indolocarbazole CEP-1347/KT-7515 into rats that have sustained ibotenic acid lesions of the nucleus basalis magnocellularis has been shown to prevent the loss of cortically-projecting neurons in that basal forebrain region. The present study tested whether this neuroprotective activity would lead to chronic sparing of a behaviour known to be impaired by that lesion, as well as to chronic maintenance of cholinergic activity in cortical target regions of the nucleus basalis. CEP-1347/KT-7515 was injected into adult rats that had sustained bilateral ibotenic acid lesions of the nucleus basalis magnocellularis; the first injection occurred 18-24 h after lesioning, with subsequent injections of CEP-1347/KT-7515 occurring every other day over 12 days. One day following the last injection the animals were tested for retention of a previously-learned delayed alternation task. Animals that received CEP-1347/KT-7515 committed significantly fewer errors than lesioned animals receiving vehicle. These same animals were tested again eight to 10 weeks later (which was 10-12 weeks post-dosing), without receiving further drug or behaviour training during the test-retest interval. The animals that had received CEP-1347/KT-7515 continued to commit significantly fewer errors than vehicle animals. Furthermore their performance at this time point was indistinguishable from normal controls. Analysis of errors showed that CEP-1347/KT-7515 prevented a lesion-induced increase in perseverative errors, suggesting the drug improved attention in the lesioned animals. Choline acetyltransferase activity in the frontal cortex of the behaviourally tested animals that received CEP-1347/KT-7515 three months previously showed a significant 40% recovery of the lesion-induced loss seen in the vehicle animals. These results demonstrate that treatment with CEP-1347/KT-7515 over 12 days following excitotoxic damage to the nucleus basalis magnocellularis produces long-term sparing of an attention-demanding behaviour.
Assuntos
Carbazóis/farmacologia , Colina O-Acetiltransferase/metabolismo , Indóis/farmacologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Substância Inominada/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/enzimologia , Lobo Frontal/fisiologia , Lateralidade Funcional , Ácido Ibotênico/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Substância Inominada/efeitos dos fármacos , Substância Inominada/patologia , Fatores de TempoRESUMO
The effect of 4 and 8 weeks treatment with 10 mg/kg/day of the thyrotropin releasing hormone analogue posatirelin (L-6-ketopiperidine-2-carbonyl-L-leucyl-proline amide) on microanatomical changes induced by monolateral and bilateral lesions of the nucleus basalis magnocellularis (NBM) were investigated. The following parameters were assessed in the frontal cortex and hippocampus of NBM-lesioned and sham-operated rats: 1) number of nerve cell and glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte profiles; 2) density of silver-gold impregnated fibres; 3) density of choline acetyltransferase (ChAT)-immunoreactive fibres; 4) intensity of acetylcholinesterase (AChE) staining. In NBM-lesioned untreated rats, no changes in the number of nerve cell or of astrocyte profiles were found either in the frontal cortex or in the hippocampus. The only exception was a decrease in the number of granule neuron profiles in the dentate gyrus at 8 weeks after lesioning. Silver-gold impregnated fibres, which express the width of interneuronal connections, were reduced in the hippocampus but not in the frontal cortex of NBM-lesioned rats. ChAT immunoreactivity and AChE reactivity, which were localised respectively in nerve fibre-like structures and in the neuropil, were decreased in the frontal cortex but not in the hippocampus from the fourth week after NBM lesioning. Lesions did not change the number of ChAT-immunoreactive nerve fibres or intensity of AChE staining in the hippocampus. Treatment with posatirelin was without effect on the number of nerve cell profiles or of GFAP-immunoreactive astrocytes both at 4 and 8 weeks after NBM lesioning. Treatment with the compound increased the number of silver-gold impregnated fibres in the hippocampus of NBM-lesioned rats and restored in part ChAT immunoreactivity and AChE reactivity in the frontal cortex. These effects were noticeable in NBM-lesioned rats after 8 weeks of treatment. The possible significance of the neuroprotective effect elicited by posatirelin treatment after lesions of the NBM is discussed.
Assuntos
Substância Inominada/efeitos dos fármacos , Hormônio Liberador de Tireotropina/análogos & derivados , Acetilcolinesterase/metabolismo , Análise de Variância , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Contagem de Células , Colina O-Acetiltransferase/metabolismo , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Lobo Frontal/citologia , Lobo Frontal/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Ouro/química , Ouro/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Fibras Nervosas/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Inclusão em Parafina , Distribuição Aleatória , Ratos , Ratos Wistar , Prata/química , Prata/metabolismo , Substância Inominada/patologia , Hormônio Liberador de Tireotropina/farmacologiaRESUMO
In the current study the neuroprotective effect of the L-type calcium channel antagonist nimodipine in rat brain was investigated in N-methyl-D-aspartate-induced neuronal degeneration in vivo. In the present model NMDA was unilaterally injected in the magnocellular nucleus basalis and the neurotoxic impact assessed by measuring cortical cholinergic fibre loss as a percentage of fibre density of the intact control hemisphere. This procedure proved to be a reproducible model in which the degree of damage was almost linearly proportional to the NMDA dose. Neuroprotection by nimodipine was determined in a number of conditions. First, the effect of nimodipine treatment in adult animals starting two weeks prior to neurotoxic injury was compared with neuroprotection provided by perinatal treatment of the mother animals with the calcium antagonist. Surprisingly, the degree of protection was in both cases similar, yielding almost 30% reduction of fibre loss. The neuroprotective effect in adulthood of perinatal nimodipine treatment may be explained by developmentally enhanced calcium binding proteins or persistent developmental changes in calcium channel characteristics. Protection by nimodipine was also investigated in aged, 26 month old rats. Compared to young adult cases, aged animals proved to be less vulnerable to NMDA exposure, while nimodipine application was more potent, thus yielding a reduction of nearly 50% in nerve fibre damage induced by NMDA infusions. Possible mechanisms of differential calcium influx in the various experimental conditions will be discussed.
Assuntos
Envelhecimento/fisiologia , Bloqueadores dos Canais de Cálcio/farmacologia , N-Metilaspartato/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Nimodipina/farmacologia , Substância Inominada/efeitos dos fármacos , Análise de Variância , Animais , Contagem de Células/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Lateralidade Funcional/fisiologia , Masculino , Ratos , Ratos Wistar , Substância Inominada/crescimento & desenvolvimento , Substância Inominada/patologiaRESUMO
Galanin is associated with multiple projection neurons, and its immunoreactivity in the cerebral cortex may be derived from diverse sources. We investigated the effects of subcortical lesions on cerebral cortical galanin concentrations. Lesions of the anterior noradrenergic bundle (ANB) comparably reduced cerebral cortical galanin and norepinephrine (NE) concentrations. The effects of the ANB lesions on galanin were immediate and became most pronounced 1 week later. Extensive unilateral lesions of the nucleus basalis of Meynert (NBM) decreased galanin concentrations, although not as markedly as after ANB lesions. The NBM lesions had no additional effect in the presence of an ANB lesion. Decreases in cerebral cortical galanin concentrations depended upon the extent and the duration of the NBM lesion and were not as pronounced as the decreases in markers of cholinergic activity. Acute treatments with physostigmine, which inhibit cerebral cortical AChE, had no effect on galanin concentrations. The depletion of galanin following an NBM lesion was most pronounced within hours of the insult, while the depletion of ChAT following the same lesions required several days to develop. Cortical concentrations of galanin and 5-HT increased 1 hr after dorsal raphe nucleus (DRN) lesions and then decreased 7 d later. Six weeks later, galanin concentrations recovered in the cerebral cortex despite the continued depletion of 5-HT. These studies suggest that a substantial portion of cerebral cortical galanin may derive from noradrenergic neurons and may be modulated by cortically-projecting ACh and 5-HT neurons.
Assuntos
Lobo Frontal/metabolismo , Neurotransmissores/metabolismo , Peptídeos/metabolismo , Animais , Aminas Biogênicas/metabolismo , Colina O-Acetiltransferase/metabolismo , Colinérgicos/metabolismo , Colinérgicos/farmacologia , Lobo Frontal/patologia , Galanina , Masculino , Neuropeptídeos/metabolismo , Norepinefrina/fisiologia , Concentração Osmolar , Ratos , Substância Inominada/patologia , Substância Inominada/fisiologia , Fatores de TempoRESUMO
The authors examined the autopsied brains from three patients who had a fatal hyperthermia syndrome. There was marked hypothalamic noradrenaline depletion in all three patients, severe brain choline acetyltransferase deficiency with nucleus basalis cell loss in two patients, and mild to moderate brain choline acetyltransferase loss in one patient. Striatal dopamine metabolite/dopamine ratio was below normal in two patients and not elevated, as would be expected after short-term neuroleptic administration, in the third. This suggests that reduced capability (aggravated by the cholinergic deficit) of the nigrostriatal dopamine system to respond adequately to stress and/or neuroleptic-induced receptor blockade may be important in the development and course of fatal hyperthermia syndrome.
Assuntos
Química Encefálica , Catatonia/metabolismo , Colina O-Acetiltransferase/análise , Dopamina/análise , Febre/metabolismo , Síndrome Maligna Neuroléptica/metabolismo , Norepinefrina/análise , Adolescente , Adulto , Autopsia , Encéfalo/enzimologia , Encéfalo/metabolismo , Encéfalo/patologia , Catatonia/patologia , Corpo Estriado/análise , Corpo Estriado/patologia , Feminino , Febre/patologia , Humanos , Hipotálamo/análise , Hipotálamo/patologia , Masculino , Pessoa de Meia-Idade , Síndrome Maligna Neuroléptica/patologia , Substância Inominada/análise , Substância Inominada/patologia , SíndromeRESUMO
Morphometric study of neurons within the magnocellular basal forebrain system (MBFS) in the three normal controls and three cases with Alzheimer's disease (AD) was studied. Immunocytochemical staining using anti-acetylcholinesterase was performed to identify the measuring areas of the MBFS, and cross sectional areas of all neurons within the MBFS in one preparation was measured making use of cresyl violet staining. About 50% of the entire neuronal cells within the MBFS were decreased and case 2 had neurofibrillary tangles in the substantia innominata. In the septal nucleus neuronal cell depopulation was observed through the all range of the neuronal cell size, and in the diagonal band of Broca neuronal cells of which cross sectional areas were more than 200 microns2 were preferentially decreased and case 3 had inverse increase of the neurons of which cross sectional areas were less than 200 microns2. In the basal nucleus of Meynert in the substantia innominata neurons of which cross sectional areas were more than 250 microns2 were markedly decreased and neurons of which cross sectional areas less than 250 microns2 were well preserved. The large neurons within the basal nucleus and diagonal band of Broca were more affected in AD. In the septal nucleus and diagonal band it was suspected that non-cholinergic neurons were also decreased and these findings suggested that other series of monoamines also bore a relationship to the dementia and neuropsychological symptoms in AD.
Assuntos
Doença de Alzheimer/patologia , Gânglios da Base/patologia , Acetilcolinesterase/metabolismo , Idoso , Doença de Alzheimer/enzimologia , Gânglios da Base/enzimologia , Contagem de Células , Feminino , Lobo Frontal/enzimologia , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/enzimologia , Neurônios/patologia , Núcleos Septais/enzimologia , Núcleos Septais/patologia , Substância Inominada/enzimologia , Substância Inominada/patologiaRESUMO
Histomorphometric analysis of age-related structural changes in the brain was performed in CW1 female mice, 3, 9, 24 and 32 months of age. Cholinergic regions, such as the hippocampus, NBM and the medial habenula (MH) were investigated in more detail focusing on morphological parameters. The thickness of the frontoparietal cortex (FPC), and the surface area of the dorsal hippocampus and the MH were found to decrease significantly from 9 to 24 months of age. Except for the unique appearance of pseudo-cysts within the FPC, the structural changes culminated by 24 months. Cells' degeneration, in the CA3 hippocampal subfield, was noted already by 9 months of age whereas in other regions the cells' surface area decreased only between 9 and 24 months. Lipofuscin accumulation was most pronounced in the large neurons of the cortex, hippocampus and NBM at 24 months of age.