RESUMO
Through metabolic imprinting mechanisms a number of bioactive molecules including polyunsaturated fatty acids affect brain functions in the developmental age and longer-lasting beneficial effects are expected. In this study pregnant rats were offered diets either containing no docosahexaenoic acid (DHA) and arachidonic acid (AA) (Placebo diet) or an excess amount of these long chain polyunsaturated fatty acids (LC-PUFA) (Supplement diet) up to the time of weaning. Bilateral N-methyl-D-aspartate (NMDA) induced neurodegeneration in the entorhinal cortex of offspring in the age of 4 months was used as a tool to investigate the neuroprotective property of the developmentally supplemented DHA and AA treatments. Hippocampus-dependent spatial learning was measured in Morris water maze and the extent of neuronal lesion in the injected brain area was evaluated. Under baseline condition, in intact or sham-lesioned rats, the Morris water maze performance was superior in the supplemented group compared to the placebo controls. NMDA-lesion in the entorhinal cortex area decreased spatial learning in the supplement-treated rats while insignificantly diminished it in the placebo controls. The same supplementation attenuated the lesion size induced by the NMDA injection into the entorhinal and ventral hippocampal areas. We concluded that LC-PUFA supplementation during fetal and early postnatal development results in long-term enhancement of spatial learning ability of the offspring and offers resistance against excitotoxic brain lesion which lasts up to the adult age.
Assuntos
Ácido Araquidônico/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Memória/efeitos dos fármacos , Animais , Suplementos Nutricionais , Avaliação Pré-Clínica de Medicamentos , Córtex Entorrinal/lesões , Feminino , Transtornos da Memória/induzido quimicamente , Microglia/efeitos dos fármacos , N-Metilaspartato , Gravidez , Ratos , Ratos WistarRESUMO
Long-chain polyunsaturated fatty acid (LC-PUFA) composition of neural membranes is a key factor for brain development, in chemical communication of neurons and probably also their survival in response to injury. Viability of cholinergic neurons was tested during brain development following dietary supplementation of fish oil LC-PUFAs (docosahexaenoic acid [DHA], eicosapentaenoic acid, arachidonic acid) in the food of mother rats. Excitotoxic injury was introduced by N-methyl-D,L-aspartate (NMDA) injection into the cholinergic nucleus basalis magnocellularis of 14-day-old rats. The degree of loss of cholinergic cell bodies, and the extend of axonal and dendritic disintegration were measured following immunocytochemical staining of cell bodies and dendrites for choline acetyltransferase and p75 low-affinity neurotrophin receptor and by histochemical staining of acetylcholinesterase-positive fibres in the parietal neocortex. The impact of different feeding regimens on fatty acid composition of neural membrane phospholipids was also assayed at 12 days of age. Supplementation of LC-PUFAs resulted in a resistance against NMDA-induced excitotoxic degeneration of cholinergic neurones in the infant rats. More cholinergic cells survived, the dendritic involution of surviving neurons in the penumbra region decreased, and the degeneration of axons at the superficial layers of parietal neocortex also attenuated after supplementing LC-PUFAs. A marked increment in DHA content in all types of phospholipids was obtained in the forebrain neuronal membrane fraction of supplemented rats. It is concluded that fish oil LC-PUFAs, first of all DHA, is responsible for the neuroprotective action on developing cholinergic neurons against glutamate cytotoxicity.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/antagonistas & inibidores , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Acetilcolinesterase/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/crescimento & desenvolvimento , Núcleo Basal de Meynert/metabolismo , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Dendritos/patologia , Ácidos Docosa-Hexaenoicos/metabolismo , Resistência a Medicamentos/fisiologia , Feminino , Alimentos Formulados , Lipídeos de Membrana/metabolismo , N-Metilaspartato/antagonistas & inibidores , Degeneração Neural/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptor de Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural/metabolismo , Resultado do TratamentoRESUMO
Evidence is presented for the potentiating role of corticosterone on axonal degeneration of serotonergic neurones during ageing. Aged rats, 24 months old, were implanted subcutaneously with 2 x 100 mg pellets of corticosterone. Serotonergic and cholinergic (ChAT- and NADPHd-positive) fibre degenerations in the anteroventral thalamic nucleus (AVT) were measured 2 months after corticosterone implantation. Numbers of immunoreactive serotonergic raphe and mesolimbic cholinergic neurones were also quantified. Basal plasma corticosterone and adrenocorticotropin (ACTH) concentrations were assayed at 2, 4, 6, and 8 weeks after implantation in the plasma and at 1, 2, 4 and 6 weeks in urine. The degree of serotonergic fibre aberrations in the AVT increased significantly after corticosterone exposure, while that of ChAT-positive and NADPHd-stained axon aberrations showed a modest but nonsignificant increase. A positive correlation between the magnitudes of serotonergic and cholinergic fibre aberrations appeared in the AVT, but only in the corticosterone-treated rats. The number of serotonin immunopositive neurones in the raphe nuclei after corticosterone decreased marginally, while that of mesopontine ChAT-positive neurones was not influenced. Measurements of basal plasma corticosterone and ACTH, as well as urine corticosterone, revealed that the steroid implantation increased the plasma corticosterone level for at least 4 weeks and decreased ACTH level for at least 6 weeks. By the week 8, the pituitary-adrenal function was apparently restored. However, at sacrifice, both the weight of adrenal glands and that of thymus remained reduced, indicating the long-lasting effects of corticosterone on target tissues. It is concluded that the raphe serotonergic neurones and their projecting fibres are sensitive to corticosterone excess in aged rats and become more vulnerable to degeneration processes than under normal ageing conditions. Cholinergic neurones of brainstem origin, which also express massive NADPHd activity, are more resistant against corticosterone, but their axon degeneration correlates to serotonergic fibre degeneration.
Assuntos
Envelhecimento , Corticosterona/administração & dosagem , Degeneração Neural , Fibras Nervosas/efeitos dos fármacos , Serotonina/fisiologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/fisiologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/urina , Animais , Axônios/química , Axônios/efeitos dos fármacos , Colina O-Acetiltransferase/análise , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/fisiologia , Corticosterona/sangue , Corticosterona/urina , Implantes de Medicamento , Cinética , Masculino , NADPH Desidrogenase/análise , Fibras Nervosas/química , Fibras Nervosas/fisiologia , Neurônios/ultraestrutura , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , Núcleos da Rafe/ultraestrutura , Ratos , Ratos Wistar , Serotonina/análise , Tálamo/ultraestruturaRESUMO
BACKGROUND AND PURPOSE: Based on the results of animal experiments, clinical trials were performed with nimodipine, which did not demonstrate a beneficial effect on outcome after stroke. The aim of this study was to determine whether the evidence from animal experiments with nimodipine supported the use of nimodipine in clinical trials. METHODS: - We performed a systematic review of animal experiments with nimodipine in focal cerebral ischemia. Studies were identified by searching Medline and Embase. We assessed whether these studies showed a beneficial effect of active treatment. In-depth analyses were performed on infarct size and amount of edema, and subgroup analyses were performed on the length of the time window to the initiation of treatment and the methodological quality of the studies. RESULTS: - Of 225 identified articles, 20 studies were included. The methodological quality of the studies was poor. Of the included studies, 50% were in favor of nimodipine. In-depth analyses showed statistically significant effects in favor of treatment (10 studies). No influence of the length of time to the initiation of treatment or of the methodological quality on the results was found. CONCLUSIONS: - We conclude that the results of this review did not show convincing evidence to substantiate the decision to perform trials with nimodipine in large numbers of patients. There were no differences between the results of the animal experiments and clinical studies. Surprisingly, we found that animal experiments and clinical studies ran simultaneously.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Nimodipina/uso terapêutico , Animais , Ensaios Clínicos como Assunto/estatística & dados numéricos , Modelos Animais de Doenças , Humanos , Reprodutibilidade dos Testes , Projetos de Pesquisa/estatística & dados numéricos , Resultado do TratamentoRESUMO
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
1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition and processing, and memory formation. A beta fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). While conflicting data exist in the literature on the roles of A beta s in the brain, and particularly in AD, recent studies have provided firm experimental evidence for the direct neurotoxic properties of A beta. 2. Sequence analysis of A beta s revealed a high degree of evolutionary conservation and inter-species homology of the A beta amino acid sequence. In contrast, synthetic A beta fragments, even if modified fluorescent or isotope-labeled derivatives, are pharmacological candidates for in vitro and in vivo modeling of their cellular actions. During the past decade, acute injection, prolonged mini-osmotic brain perfusion approaches or A beta infusions into the blood circulation were developed in order to investigate the effects of synthetic A beta s, whereas transgenic models provided insight into the distinct molecular steps of pathological APP cleavage. 3. The hippocampus, caudate putamen, amygdala and neocortex all formed primary targets of acute neurotoxicity screening, but functional consequences of A beta infusions were primarily demonstrated following either intracerebroventricular or basal forebrain (medial septum or magnocellular basal nucleus (MBN)) infusions of A beta fragments. 4. In vivo investigations confirmed that, while the active core of A beta is located within the beta(25-35) sequence, the flanking peptide regions influence not only the folding properties of the A beta fragments, but also their in vivo neurotoxic potentials. 5. It has recently been established that A beta administration deranges neuron-glia signaling, affects the glial glutamate uptake and thereby induces noxious glutamatergic stimulation of nerve cells. In fact, a critical role for N-methyl-D-aspartate (NMDA) receptors was postulated in the neurotoxic processes. Additionally, A beta s might become internalized, either after their selective binding to cell-surface receptors or after membrane association in consequence of their highly lipophilic nature, and induce free radical generation and subsequent oxidative injury. Ca(2+)-mediated neurotoxic events and generation of oxygen free radicals may indeed potentiate each other, or even converge to the same neurotoxic events, leading to cell death. 6. Neuroprotection against A beta toxicity was achieved by both pre- and post-treatment with NMDA receptor channel antagonists. Moreover, direct radical-scavengers, such as vitamin E or vitamin C, attenuated A beta toxicity with high efficacy. Interestingly, combined drug treatments did not necessarily result in additive enhanced neuroprotection. 7. Similarly to the blockade of NMDA receptors, the neurotoxic action of A beta s could be markedly decreased by pharmacological manipulation of voltage-dependent Ca(2+)-channels, serotonergic IA or adenosine A1 receptors, and by drugs eliciting membrane hyperpolarization or indirect blockade of Ca(2+)-mediated intracellular consequences of intracerebral A beta infusions. 8. A beta neurotoxicity might be dose-dependently modulated by trace metals. In spite of the fact that zinc (Zn) may act as a potent inhibitor of the NMDA receptor channel, high Zn doses accelerate A beta fibril formation, stabilize the beta-sheet conformation and thereby potentiate A beta neurotoxicity. Combined trace element supplementation with Se, Mn, or Mg, which prevails over the expression of detoxifying enzymes or counteracts intracellular elevations of Ca2+, may reduce the neurotoxic impact of A beta s. 9. Alterations in the regulatory functions of the hypothalamo-pituitary-adrenal axis may contribute significantly to neurodegenerative changes in the brain. Furthermore, AD patients exhibit substantially increased circadia
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Humanos , Fármacos Neuroprotetores/farmacologiaRESUMO
We determined whether food restriction or the drugs nimodipine (Ca2+ antagonist) and deprenyl (a MAO-B inhibitor) prevent the development of stroke in the spontaneously hypertensive stroke-prone rat (SHR-SP). Forty male SHR-SP rats, in the age of 34 weeks, were exposed to various treatments. During a period of 27 weeks, survival and blood pressure were followed. In the control and deprenyl group, the blood pressure values remained unchanged; 50% had died after 27 weeks. All rats that were treated with nimodipine survived. After food restriction, 7/8 rats survived and showed a lower blood pressure. This study in SHR-PR rats shows the superiority of nimodipine on survival, and the potential of food restriction as a stroke-preventing measure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Transtornos Cerebrovasculares/fisiopatologia , Privação de Alimentos/fisiologia , Longevidade/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Nimodipina/farmacologia , Selegilina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Transtornos Cerebrovasculares/genética , Expectativa de Vida , Masculino , Ratos , Ratos Endogâmicos SHR , Análise de SobrevidaRESUMO
Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca2+ channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potential of this combined drug treatment before and after NMDA-exposure. NMDA was unilaterally injected in the magnocellular nucleus basalis (MBN). Neuronal damage was assessed 12 days after the NMDA-injection by measuring the reduction of cholinergic cortical fibres that originate from the MBN neurons. In controls that received no drug treatment, NMDA-exposure damaged MBN neurons such that 66% of the cholinergic terminals were lost in the ipsilateral parietal cortex. Pretreatment with a nimodipine diet (860 ppm) combined with application of MK-801 (5 mg/kg i.p.) before NMDA-exposure reduced fibre loss by 89% thereby providing a near complete neuroprotection. Combined therapy of MK-801 (5 mg/kg i.p.) and nimodipine (15 mg/kg i.p.) 8 min after NMDA-infusion reduced neuronal injury by 82%, while the same combination given 2 h after the excitotoxic treatment still yielded a 66% protection against neurotoxic damage invoked by NMDA. In conclusion, the present data show that a dual blockade of NMDA-channels and voltage-dependent calcium channels (VDCC's) up to 2 h after NMDA-exposure is able to provide a significant protection against NMDA-neurotoxicity.
Assuntos
Envelhecimento/fisiologia , Encéfalo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , N-Metilaspartato/toxicidade , Degeneração Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nimodipina/farmacologia , Análise de Variância , Animais , Encéfalo/patologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , N-Metilaspartato/antagonistas & inibidores , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Neurônios/patologia , Ratos , Ratos WistarRESUMO
Beta-amyloid(1-42) peptide (betaAP) was injected into the right nucleus basalis magnocellularis (nbm) of rats. After a 14-day survival time, the acetylcholinesterase and choline acetyltransferase activities and the number of muscarinic receptors were found biochemically to be significantly reduced in the ipsilateral frontal cortices. Confirmation of these data with silver staining also revealed degeneration of the projective fibers of the nbm to the frontal cortex. These results demonstrate the cholinotoxicity of betaAP in an in vivo animal model.
Assuntos
Precursor de Proteína beta-Amiloide/farmacologia , Colina O-Acetiltransferase/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Substância Inominada/efeitos dos fármacos , Acetilcolinesterase/efeitos dos fármacos , Animais , Ligação Competitiva , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
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
Postnatal development of ingrowing cholinergic and serotonergic fiber patterns were studied in the rat hippocampus and parietal cortex employing a histochemical procedure for acetylcholinesterase as a cholinergic fiber marker, and immunocytochemistry of serotonin for serotonergic fiber staining. The rat pups were killed at postnatal days 1, 3, 5, 7, 10, and 20. The development of cholinergic and serotonergic innervation was described and the fiber density quantified under normal conditions and after long-term prenatal anemic hypoxia induced by chronic exposure to sodium nitrite. Furthermore, a third group was studied in which the nitrite hypoxia was combined with a simultaneous treatment with the Ca(2+)-entry blocker nimodipine to test the neuroprotective potential of this drug. Quantitative measurement of fiber density from postnatal day 1 to day 20 yielded the following results: (i) both neurotransmitter systems revealed an age-dependent and an anatomically-organized developmental pattern; (ii) the serotonergic innervation of the dorsal hippocampus preceded that of cholinergic afferentation in postnatal days 1-3; (iii) prenatal hypoxia induced a transient delay in the innervation of parietal neocortex and dentate gyrus for both neurotransmitter systems, but left the innervation of the cornu ammonis unaffected; and (iv) the hypoxia-induced retardation of cholinergic and serotonergic fiber development was prevented by concomitant application of the Ca(2+)-antagonist nimodipine during the hypoxia. The results indicate that prenatal hypoxia evokes a temporary delay in the cholinergic and serotonergic fiber outgrowth in cortical target areas in a region-specific manner. The hypoxia-induced growth inhibition is prevented by the calcium antagonist nimodipine, which supports the importance of the intracellular Ca2+ homeostasis of cells and growth cones in regulating axonal proliferation.
Assuntos
Acetilcolinesterase/metabolismo , Envelhecimento/fisiologia , Córtex Cerebral/fisiologia , Hipóxia Fetal/fisiopatologia , Hipocampo/fisiologia , Nimodipina/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Serotonina/metabolismo , Nitrito de Sódio/toxicidade , Acetilcolinesterase/análise , Animais , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/fisiopatologia , Feminino , Hipóxia Fetal/induzido quimicamente , Hipocampo/crescimento & desenvolvimento , Hipocampo/fisiopatologia , Imuno-Histoquímica , Fibras Nervosas/fisiologia , Gravidez , Ratos , Ratos Wistar , Valores de Referência , Serotonina/análiseRESUMO
At the ultrastructural level different anomalies of the cerebral microvasculature were encountered in the brains of aged rats. These aberrations can either be attributed to degeneration processes or to the perivascular deposition of, e.g., collagen fibrils and other, unidentified, proteinous debris. We previously reported that chronic treatment with the calcium antagonist nimodipine from 24-30 months especially reduced the incidence of aging-related microvascular deposits in the frontoparietal motor cortex of rats. The same drug treatment did not interfere with the degeneration of pericytes. The reduction of the microvascular depositions was, however, not consistent throughout different cortical layers. We now demonstrate that an earlier onset (16-30 months) of the drug application yields a prominent and consistent reduction of microvascular deposits for all cortical layers studied. The earlier onset of the drug treatment again did not influence the quantity of pericyte degeneration. The effect of long-term nimodipine treatment (16-30 months) was also examined in the sciatic nerve. Compared to young animals the sciatic nerve of aged control rats (30 months) showed a variety of alterations of myelinated fiber (MF) morphometry. Nimodipine treatment from 16-30 months did not significantly change these morphometric aging-related changes. Approximately 6% of the MF in aged rats display morphological myelin irregularities. After nimodipine application the frequency of these alterations was reduced, which was, however, only significant for partial demyelination known as myelin ballooning. These results indicate a consistent influence of nimodipine on cerebral microvessels, while there is only a moderate effect on the morphology of sciatic myelinated fibers during the aging process.
Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Nimodipina/farmacologia , Nervo Isquiático/efeitos dos fármacos , Animais , Membrana Basal/efeitos dos fármacos , Membrana Basal/ultraestrutura , Capilares/efeitos dos fármacos , Masculino , Córtex Motor/efeitos dos fármacos , Córtex Motor/ultraestrutura , Bainha de Mielina/efeitos dos fármacos , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/ultraestrutura , Ratos , Ratos Endogâmicos , Nervo Isquiático/ultraestruturaRESUMO
The projections from the Ammon's horn to the cholinergic cell groups in the medial septal and diagonal band nuclei were investigated with anterograde tracing of Phaseolus vulgaris leucoagglutinin combined with immunocytochemical detection of choline acetyltransferase, in the rat. Tracer injections were placed into various fields of the septal and temporal parts of the Ammon's horn (CA1-3). These injections revealed differential distributions of Phaseolus vulgaris leucoagglutinin-labeled projections in both the lateral septal area and the medial septum-diagonal band complex. In addition to the labeling of dense axonal networks in the lateral septal area, significant numbers of arborizing fibers were labeled in the medial septal and diagonal band nuclei, in particular after tracer injections into the fields CA2-3. The distributions of the projections to the medial septum-diagonal band complex arising from the septal portion of fields CA1 and CA2-3 are similar. In contrast, the septal part and temporal portion of field CA3 project in a topographically differentiated manner to the medial septum and nuclei of the diagonal band. The septal pole of the Ammon's horn innervates the dorsal and medial parts of the medial septal nucleus and the anterior and dorsal parts of the vertical limb of the diagonal band. Axons of the temporal pole of the hippocampus reach the lateral and ventral parts of the medial septum and the intermediate, caudal and ventral parts of the vertical limb of the diagonal band. These results demonstrate direct feedback projections of the Ammon's horn to the medial septum-diagonal band complex, which show a topographic organization mainly as a function of the septotemporal level of the hippocampus. Within the medial septal and diagonal band nuclei, the labeled varicosities are formed in close proximity to the cell bodies and dendrites of the cholinergic neurons.
Assuntos
Lobo Frontal/fisiologia , Hipocampo/fisiologia , Vias Neurais/fisiologia , Septo Pelúcido/fisiologia , Animais , Colina O-Acetiltransferase/metabolismo , Hipocampo/enzimologia , Imuno-Histoquímica , Masculino , Neurônios/enzimologia , Neurônios/fisiologia , Sistema Nervoso Parassimpático/citologia , Sistema Nervoso Parassimpático/fisiologia , Fito-Hemaglutininas , Ratos , Ratos Endogâmicos , Transmissão SinápticaRESUMO
The prefrontal cortex (PFC) projections to the basal forebrain cholinergic cell groups in the medial septum (MS), vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB), and the magnocellular basal nucleus (MBN) in the rat were investigated by anterograde transport of Phaseolus vulgaris leuco-agglutinin (PHA-L) combined with acetylcholinesterase (AChE) histochemistry or choline acetyltransferase (ChAT) immunocytochemistry. The experiments revealed rich PHA-L-labeled projections to discrete parts of the basal forebrain cholinergic system (BFChS) essentially originating from all prefrontal areas investigated. The PFC afferents to the BFChS display a topographic organization, such that medial prefrontal areas project to the MS, VDB, and the medial part of the HDB, whereas the orbital and agranular insular areas predominantly innervate the HDB and MBN, respectively. Since the recurrent BFChS projection to the prefrontal cortex is arranged according to a similar topography, the relationship between the BFChS and the prefrontal cortex is characterized by reciprocal connections. Furthermore, tracer injections in the PFC resulted in anterograde labeling of numerous "en passant" and terminal boutons apposing perikarya and proximal dendrites of neurons in the basal forebrain, which were stained for the cholinergic marker enzymes. These results indicate that prefrontal cortical afferents make direct synaptic contacts upon the cholinergic neurons in the basal forebrain, although further analysis at the electron microscopic level will be needed to provide conclusive evidence.
Assuntos
Acetilcolina/fisiologia , Diencéfalo/anatomia & histologia , Lobo Frontal/anatomia & histologia , Neurônios/química , Telencéfalo/anatomia & histologia , Acetilcolinesterase/análise , Animais , Colina O-Acetiltransferase/análise , Retroalimentação , Masculino , Vias Neurais/anatomia & histologia , Fito-Hemaglutininas , Ratos , Ratos Endogâmicos , Terminologia como AssuntoRESUMO
We studied the effects of long-term treatment with 1,4-dihydropyridine nimodipine on age-related changes of the cerebral microvasculature in layers I, III, and V of the frontoparietal motor cortex of aged (30 months) male Wistar rats. Ultrastructural alterations of microvessels can either be attributed to degeneration or to deposition processes. Nimodipine application, irrespective of the time of onset, did not interfere with the degeneration of microvascular pericytes. However, nimodipine treatment from 24-30 months significantly reduced the amount of microvascular deposition products in cortical layers I and III, while an earlier onset (16 months) of the drug application resulted in a significant reduction in all motor cortex layers studied. This indicates a different susceptibility of microvessels in layer V of the frontoparietal motor cortex. These results show a beneficial effect of nimodipine on the integrity of cerebral microvasculature during aging and may provide a morphologic basis for the improved motor and cognitive performance in aged rats after chronic nimodipine application.
Assuntos
Envelhecimento , Encéfalo/irrigação sanguínea , Microcirculação/ultraestrutura , Nimodipina/farmacologia , Animais , Masculino , Microcirculação/efeitos dos fármacos , Microscopia Eletrônica , Nimodipina/administração & dosagem , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
In the present study the effects of long-term treatment with the 1,4-dihydropyridine calcium antagonist nimodipine on ultrastructural alterations of the microvascular morphology were examined in the frontoparietal cortex, entorhinal cortex and CA1 of the hippocampus in the aged rat. Qualitative observations of cerebral microvasculature of aged (30 months) Wistar rats revealed the presence of microvascular fibrosis, membranous inclusions within the basement membrane and basement membrane thickenings. In several cortical regions the percentage of aberrant microvessels was significantly reduced in the nimodipine-treated rats. The observed microvascular anomalies were classified into five distinct categories of which microvascular fibrosis type II, defined as collagen deposits up to 1 micron within the microvascular basement membrane, showed the strongest reduction in the nimodipine-treated cases. The decrement of the percentage of aberrant microvessels and the relative occurrence of several classes of microvascular deviations showed some variation in the various brain regions examined and was most pronounced in frontoparietal cortex layer III. These results may provide a morphological basis for the improved motor and cognitive performance in aged rats after long-term oral nimodipine administration.
Assuntos
Envelhecimento/fisiologia , Córtex Cerebral/irrigação sanguínea , Hipocampo/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Nimodipina/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/ultraestrutura , Di-Hidropiridinas/administração & dosagem , Di-Hidropiridinas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Masculino , Nimodipina/administração & dosagem , Ratos , Ratos EndogâmicosRESUMO
A detailed analysis of the cortical projections of the medial septum-diagonal band (MS/DB) complex was carried out by means of anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). The tracer was injected iontophoretically into cell groups of the medial septum (MS) and the vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB), and sections were processed immunohistochemically for the intra-axonally transported PHA-L. The labeled efferents showed remarkable differences in regional distribution in the cortical mantle dependent on the position of the injection site in the MS/DB complex, revealing a topographic organization of the MS/DB-cortical projection. In brief, the lateral and intermediate aspects of the HDB, also referred to as the magnocellular preoptic area, predominantly project to the olfactory nuclei and the lateral entorhinal cortex. The medial part of the HDB and adjacent caudal (angular) part of the VDB are characterized by widespread, abundant projections to medial mesolimbic, occipital, and lateral entorhinal cortices, olfactory bulb, and dorsal aspects of the subicular and hippocampal areas. Projections from the rostromedial part of the VDB and from the MS are preponderantly aimed at the entire hippocampal and retrohippocampal regions and to a lesser degree at the medial mesolimbic cortex. Furthermore, the MS projections are subject to a clear mediolateral topographic arrangement, such that the lateral MS predominantly projects to the ventral/temporal aspects of the subicular complex and hippocampus and to the medial portion of the entorhinal cortex, whereas more medially located cells in the MS innervate more septal/dorsal parts of the hippocampal and subicular areas and more lateral parts of the entorhinal cortex. PHA-L filled axons have been observed to course through a number of pathways, i.e., the fimbria-fornix system, supracallosal stria, olfactory peduncle, and lateral piriform route (the latter two mainly by the HDB and caudal VDB). Generally, labeled projections were distributed throughout all cortical layers, although clear patterns of lamination were present in several target areas. The richly branching fibers were abundantly provided with both "boutons en passant" and terminal boutons. Both distribution and morphology of the labeled basal forebrain efferents in the prefrontal, cingulate, and occipital cortices closely resemble the distribution and morphology of the cholinergic innervation as revealed by immunohistochemical demonstration of choline acetyltransferase. In contrast, the labeled projections to the olfactory, hippocampal, subicular, and entorhinal areas showed a heterogeneous morphology. Here, the distribution of only the thin varicose projections resembled the distribution of cholinergic fibers.
Assuntos
Encéfalo/citologia , Lobo Frontal/citologia , Animais , Mapeamento Encefálico , Masculino , Vias Neurais/anatomia & histologia , Fito-Hemaglutininas , Ratos , Ratos EndogâmicosRESUMO
The course of the ascending pathways originating from the anterior gustatory and posterior visceral sensory part of the solitary tract nucleus and the topographic organization of the projections to the hypothalamus in the rat were studied with anterogradely transported Phaseolus vulgaris lectin. In general, the posterior visceral sensory part of the solitary tract nucleus has ascending projections as far as the septum-diagonal band complex and gives rise to heavy input to the bed nucleus of the stria terminals, and to the dorsomedial and paraventricular hypothalamic nuclei. A more moderate projection is aimed at a variety of other hypothalamic nuclei, to the medial and central amygdaloid nuclei and to the paraventricular nucleus of the thalamus. The ventromedial hypothalamic nucleus is strikingly missing an afferent input from the nucleus of the solitary tract. Furthermore, it was shown that whereas the caudal solitary tract nucleus has predominant long ascending connections, the projections from the anterior taste related region of the nucleus of the solitary tract have only limited forebrain projections which do not reach beyond the level of the anterior dorsal hypothalamic nucleus.
Assuntos
Hipotálamo/citologia , Bulbo/citologia , Animais , Masculino , Vias Neurais/anatomia & histologia , Fito-Hemaglutininas , Ratos , Ratos EndogâmicosRESUMO
The hypothalamus fulfills multiple functions, e.g., integration of food and water ingestion, various forms of social behavior and physiological neuroendocrine activities. Hypothalamic areas, particularly the ventromedial, lateral and paraventricular areas (VMH, LHA and PVN respectively), that contribute to the regulation of food intake are also involved in the regulation of blood glucose and plasma free fatty acid (FFA) levels. This regulation is controlled both directly via neural pathways and indirectly by hormones, e.g., insulin, glucagon, norepinephrine (NE) and epinephrine (E). A description is presented of the intrahypothalamic connections and the pathways between the hypothalamus and the motor areas of both the sympathetic system in the spinal cord (the intermediolateral column IML) and the parasympathetic system in the brainstem (the dorsal motornucleus of the vagus and the nucleus ambiguus). Noradrenergic stimulation of the LHA, VMH and PVN can alter blood glucose, plasma FFA and insulin levels independently of each other, e.g., noradrenergic stimulation of the VMH leads to an increase of insulin, glucose and FFA. Exercise induced increases of glucose are suppressed by alpha-adrenergic blockade of the LHA, VMH and PVN. Alpha-adrenergic blockade of the VMH during exercise causes an exaggerated increase of plasma FFA whereas alpha-blockade of both the LHA and PVN does not change the normal exercise induced increase of plasma FFA. The apparent contradiction that both adrenergic stimulation and adrenergic blockade of the VMH result in an increase in FFA may be explained by assuming postsynaptic alpha- and beta-adrenergic receptors in the VMH controlling glucose and FFA release respectively and FFA release and presynaptic inhibitory alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glicemia/metabolismo , Ingestão de Alimentos , Ácidos Graxos não Esterificados/sangue , Hipotálamo/fisiologia , Animais , Sistema Nervoso Autônomo/fisiologia , Mapeamento Encefálico , Núcleo Hipotalâmico Dorsomedial/fisiologia , Região Hipotalâmica Lateral/fisiologia , Ratos , Resposta de Saciedade/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologiaRESUMO
We investigated the projection from the infralimbic division of the prefrontal cortex (area 25) to histaminergic neurons in the posterior hypothalamic area. Phaseolus vulgaris-leucoagglutinin (PHA-L) was injected in the prefrontal cortex of rats. Frozen brain sections were subjected to combined PHA-L and histidine decarboxylase (HDC)-peroxidase immunocytochemistry, using nickel-enhanced diaminobenzidine (blue reaction product) to visualize the transported PHA-L, and diaminobenzidine (brown reaction product) to visualize simultaneously the HDC-containing neurons. PHA-L-labeled fibers could be seen coursing in the capsula interna, leaving the telencephalon via the anterior thalamic radiation and the medial forebrain bundle. In the lateral and posterior hypothalamic areas, PHA-L-labeled fibers leave the medial forebrain bundle and traverse the nuclei containing HDC-immunoreactive neurons. Varicosities on the PHA-L-labeled fibers, the majority of which occur en passant, could be observed in close association with the HDC-immunoreactive neurons. The results suggest that the hypothalamic histaminergic neurons receive afferent synaptic input from neurons of the infralimbic division of the prefrontal cortex.