RESUMO
Ethanol exposure during pregnancy is one of the major causes of mental retardation in western countries by inducing fetal-alcohol-like-syndromes. Red wine is known to contain ethanol but also compounds with putative antioxidant properties. It has also been shown that nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are severely affected by ethanol during prenatal and postnatal life. The aim of the current study was to investigate in male CD1 mice brain alterations in NGF and BDNF due to chronic early exposure to ethanol solution (11 vol%) or to red wine at the same alcohol concentration starting from 60 days before pregnancy up to pups weaning. Data revealed no differences between groups of dams in pregnancy duration, neither in pups delivery, pups mortality and sex ratio. Data also showed that adult animals exposed to only ethanol had disrupted levels of both NGF and BDNF in the hippocampus and other brain areas. This profile was associated with impaired ChAT immunopositivity in the septum and Nuclei Basalis and with altered cognition and emotional behavior. Quite interestingly mice exposed to red wine had no change in the behavior or in ChAT immunopositivity but a decrease in hippocampal BDNF and a mild NGF decrease in the cortex. Also NGF-induced neuritic outgrowth in PC-12 cells was still present when exposed to red wine but not when exposed to ethanol solution only. Data suggest differences in ethanol-induced neurotoxicity between red wine and ethanol solution only.
Assuntos
Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Etanol/toxicidade , Troca Materno-Fetal , Fator de Crescimento Neural/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Colina O-Acetiltransferase/análise , Cognição/efeitos dos fármacos , Emoções/efeitos dos fármacos , Etanol/administração & dosagem , Etanol/sangue , Feminino , Masculino , Camundongos , Gravidez , Vinho/efeitos adversosRESUMO
SUMMARY: Rats exposed during prenatal life to methylazoxymethanol (MAM) display in postnatal age structural and behavioral deficits resembling those observed in schizophrenic patients. These deficits are associated with significant changes in brain nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), particularly in the hippocampus and entorhinal cortex. In the present study, we used the MAM model to investigate in young rats the effect of antipsychotics, Clozapine and Haloperidol, on brain and blood NGF and BDNF presence. Young animals were used because administration of antipsychotics during adolescence is a common feature of intervention. The results showed that administration of Clozapine and Haloperidol causes significant changes in the concentration of NGF and BDNF in the brain and bloodstream of MAM-treated rats. These findings indicate that these drugs may affect the synthesis and release of neurotrophins in the central nervous system and in the blood circulation. In addition, the MAM model can be a useful tool to investigate the biochemical and molecular mechanisms regarding the effects of antipsychotics.
Assuntos
Alquilantes , Antipsicóticos/farmacologia , Química Encefálica/efeitos dos fármacos , Clozapina/farmacologia , Córtex Entorrinal/patologia , Haloperidol/farmacologia , Hipocampo/patologia , Acetato de Metilazoximetanol/análogos & derivados , Fatores de Crescimento Neural/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Córtex Entorrinal/anormalidades , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Hipocampo/anormalidades , Fatores de Crescimento Neural/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-DawleyRESUMO
It has been shown that conjunctivally applied NGF in rats can reach the retina and optic nerve. Whether topical eye NGF application reaches the central nervous system is not known. In the present study, we have addressed this question. It was found that topical eye NGF application affects brain cells. Time-course studies revealed that repeated NGF application leads to high concentration of this neurotrophins after 6 h and normal levels after 24 h. Our results also showed that topical eye application of NGF causes an enhanced expression of NGF receptors and ChAT immunoreactivity in forebrain cholinergic neurons, suggesting that ocular NGF application could have a functional role on damaged brain cells. The present findings suggest that eye NGF application can represent an alternative route to prevent degeneration of NGF-receptive neurons involved in disorders such as Alzheimer and Parkinson.
Assuntos
Vias Aferentes/efeitos dos fármacos , Núcleo Basal de Meynert/efeitos dos fármacos , Túnica Conjuntiva/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Soluções Oftálmicas/farmacologia , Núcleos Septais/efeitos dos fármacos , Vias Aferentes/metabolismo , Animais , Núcleo Basal de Meynert/metabolismo , Contagem de Células , Líquido Cefalorraquidiano/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Colina O-Acetiltransferase/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/metabolismo , Túnica Conjuntiva/inervação , Túnica Conjuntiva/metabolismo , Feminino , Masculino , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Soluções Oftálmicas/metabolismo , Soluções Oftálmicas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural/efeitos dos fármacos , Receptor de Fator de Crescimento Neural/metabolismo , Artéria Retiniana/efeitos dos fármacos , Artéria Retiniana/fisiologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Núcleos Septais/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
The aim of the present study was to investigate the variations in leptin and nerve growth factor (NGF) expression induced by immobilization stress in the brain of male and female adult CD1 mice. We found that 10 days of repeated immobilization stress induced an increase of hypothalamus and thalamus NGF that was more pronounced in female than in male mice. We also found that this type of stress induced an increase of leptin expression in the hypothalamus of female mice, and a decrease in the thalamus of both male and female mice, associated with enhanced expression of leptin receptors in the hypothalamus and thalamus, both in male and female mice. The observation that the brain leptin and NGF receptors were altered by stress suggests a functional role for these molecules in neuroendocrine and cardiovascular response to stress events.
Assuntos
Encéfalo/metabolismo , Leptina/metabolismo , Fator de Crescimento Neural/metabolismo , Caracteres Sexuais , Estresse Psicológico/metabolismo , Animais , Encéfalo/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Regulação para Baixo/fisiologia , Metabolismo Energético/fisiologia , Feminino , Hipotálamo/metabolismo , Hipotálamo/fisiopatologia , Masculino , Camundongos , Sistemas Neurossecretores/fisiopatologia , Receptores para Leptina/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Estresse Psicológico/fisiopatologia , Tálamo/metabolismo , Tálamo/fisiopatologia , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: Nerve growth factor (NGF) has been indicated to be critical to normal renal development in rodents. However, little is known about the expression of NGF and the high-affinity NGF receptors in human kidneys which is essential for promoting the biological and functional activities of NGF. The present study examined the presence of NGF, low-affinity (p75) and high-affinity tyrosine kinase A (TrkA) NGF receptor (NGFR) immunoreactivity in diseased human kidneys. METHODS: Renal biopsies were performed in 24 patients (11 females and 13 males, ranging from 12 to 78 years of age), with various renal diseases. Kidney biopsy samples were fixed in Bouin fluid for 24 hours, washed, dehydrated, embedded in paraplast sections (3-micron thick) and immunostained for NGF, TrkA and p75 localization. Immunostained sections were evaluated under a Nikon Eclipse E600 microscope equipped with a x20 objective and a Nikon DMX 1200 digital camera connected to a PC computer, with the aid of a computerized image analysis system. RESULTS: The results demonstrate the existence of NGF and TrkA in tubular and glomerular cells and of p75-positivity in the interstitial and mesangial cells. It also shows colocalization of TrkA and NGF, but not TrkA and p75 in tubular and glomerular cells, implying that the synthesis and utilization of NGF might be autocrinally regulated. CONCLUSIONS: These findings suggest that NGF signaling may be important in human kidney and glomerular response to injury, though to understand the precise functional significance of these NGF elements in the human kidney, further studies need to be done.
Assuntos
Nefropatias/metabolismo , Rim/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , Adolescente , Adulto , Idoso , Criança , Feminino , Imunofluorescência , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Humanos , Imuno-Histoquímica , Rim/patologia , Nefropatias/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
Changes during gestation have been shown to induce brain maldevelopment associated with changes in neurotrophins as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neuropsychiatric disorders in humans. A rat model of altered prenatal brain development resembling the onset of schizophrenia has been obtained by administering in fetus methylazoxymethanol (MAM) at gestational day 12 which impairs the growth of limbic pathways between the entorhinal cortex and the hippocampus. Using the MAM model we studied in young rats the brain levels of both NGF/BDNF and their main receptors, TrkA/TrkB, to investigate whether or not changes in neurotrophins could affect the presence of brain BrdU positive cells. We found increased NGF and BDNF protein levels, associated with elevated TrkA and TrkB expression, in the hippocampus, entorhinal cortex, olfactory lobes and subventricular zone (SVZ), brain areas playing a key role in the production and migration of new dividing cells. We also found higher levels of BrdU positive cells in the SVZ and hippocampus but not a significant potentiation in the entorhinal cortex and olfactory lobes. All together the findings indicate that prenatal MAM exposure in young rats may elicit both neurotrophins' elevation and cell proliferation in limbic brain areas.
Assuntos
Encéfalo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião de Mamíferos , Acetato de Metilazoximetanol/análogos & derivados , Fatores de Crescimento Neural/metabolismo , Teratogênicos/farmacologia , Análise de Variância , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Feminino , Acetato de Metilazoximetanol/farmacologia , Fatores de Crescimento Neural/classificação , Gravidez , Ratos , Receptor trkA/metabolismo , Receptor trkB/metabolismoRESUMO
BACKGROUND: Early experiences produce persistent changes in brain and behavioral function. We investigate whether being reared in a communal nest (CN), a form of early social enrichment that characterizes the natural ecological niche of many rodent species including the mouse, has effects on adult social/aggressive behavior and nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in mice. METHODS: The CN consisted of a single nest where three mothers kept their pups together and shared care-giving behavior from birth to weaning (postnatal day 25). RESULTS: Compared to standard laboratory conditions, in CN condition, mouse mothers displayed higher levels of maternal care. At adulthood, CN mice displayed higher propensity to interact socially and achieved more promptly the behavioral profile of either dominant or subordinate male. Furthermore, CN adult mice showed higher NGF levels, which were further affected by social status, and higher BDNF levels in the brain. CONCLUSIONS: Our findings indicate that CN, a highly stimulating early social environment, produces differences in social behavior later in life associated with marked changes of neurotrophin levels in selected brain areas, including hippocampus and hypothalamus.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Fator de Crescimento Neural/metabolismo , Comportamento Social , Meio Social , Fatores Etários , Agressão/fisiologia , Animais , Feminino , Masculino , Comportamento Materno/fisiologia , CamundongosRESUMO
We investigated the effect of glaucoma (GL) on nerve growth factor (NGF) presence in two brain visual areas. Rats with elevated intraocular pressure (EIOP), induced by hypertonic saline injection in the episcleral vein, were treated with eye topical application of saline or NGF. Rats were subsequently sacrificed, and brain tissues were used for immunohistochemical, biochemical, and molecular analyses. We found that GL alters the basal level of NGF and NGF receptors in brain visual centers and that NGF eye application normalized these deficits. These findings demonstrate that the reduced presence of NGF can arise due to degenerative events in retinal and brain visual areas.
Assuntos
Corpos Geniculados/metabolismo , Glaucoma/metabolismo , Fator de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Córtex Visual/metabolismo , Administração Tópica , Animais , Western Blotting/métodos , Corpos Geniculados/química , Imuno-Histoquímica , Masculino , Modelos Animais , Fator de Crescimento Neural/análise , Fator de Crescimento Neural/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor trkA/análise , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/análise , Córtex Visual/químicaRESUMO
Chronic stress and increased sympathetic nerve activity have been associated with cardiovascular disorders such as hypertension, myocardial infarction and stroke. The aim of this study was to investigate the role of nerve growth factor (NGF) on the expression of tyrosine hydroxylase (TH), vascular-endothelial growth factor (VEGF) and leptin receptor (OB-R) in brain, adrenal and cardiovascular tissues of adult male and female mice following a chronic stress procedure. It was found that daily restraint for 10 consecutive days alters TH levels in hypothalamic and brainstem areas related to sympathetic activation, in both male and female mice. Chronic stress procedure also modifies heart and aorta VEGF levels in male mice, and adrenal glands TH in female mice. The NGF administration in stressed mice reverted the stress-induced up-regulation of TH levels in male and female mice hypothalamic nuclei and in male locus coeruleus. Administration of NGF in stressed animals also down-regulated OB-R levels in the hypothalamus of both male and female mice and in the female aorta. Our findings indicate that repeated restraint in mice has an effect on TH and VEGF protein content at different brain and peripheral sites involved in the sympathetic and cardio-vascular response to stressful stimuli. NGF administration is able to counteract some of these stress-induced changes. Since NGF is known to be up-regulated during stress, a possible functional significance of our observations is that the circulating NGF released during and following stress may serve to prevent possible deficits and/or damage linked to stress-induced sympathetic and cardiovascular activation.
Assuntos
Aorta/metabolismo , Miocárdio/metabolismo , Fator de Crescimento Neural/administração & dosagem , Restrição Física/métodos , Caracteres Sexuais , Estresse Psicológico , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Feminino , Coração/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Camundongos , Receptores para Leptina/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
We have recently shown that conjunctivally applied nerve growth factor (NGF) in rats can reach the retina, the optic nerve and the CNS. In the present study, we investigated whether NGF application as collyrium can promote the recovery of chemically injured basal forebrain cholinergic neurons. NGF was administered on the eye of adult male mice previously treated i.c.v. with ibotenic acid to impair cholinergic pathways. Mice were tested in the passive avoidance test, and after 2 weeks of NGF administration were killed and the brains used for structural, biochemical and molecular analyses. The results showed that application of NGF on the eye surface protected choline acetyl transferase levels. These findings strengthen the hypothesis that application of NGF on the eye can represent an alternative delivery route to promote the recovery of brain cells during degeneration, including neurons involved in learning and memory activities.
Assuntos
Núcleo Basal de Meynert/efeitos dos fármacos , Fibras Colinérgicas/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Fator de Crescimento Neural/administração & dosagem , Neurônios/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Acetilcolina/biossíntese , Animais , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/fisiopatologia , Córtex Cerebral/enzimologia , Colina O-Acetiltransferase/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/patologia , Denervação , Modelos Animais de Doenças , Hipocampo/enzimologia , Ácido Ibotênico , Injeções Intraventriculares , Masculino , Camundongos , Degeneração Neural/induzido quimicamente , Degeneração Neural/prevenção & controle , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Soluções Oftálmicas , Recuperação de Função Fisiológica/fisiologia , Resultado do TratamentoRESUMO
Early experiences affect brain function and behavior at adulthood. Being reared in a communal nest (CN), consisting of a single nest where three mothers keep their pups together and share care-giving behavior from birth to weaning (postnatal day [PND] 25), provides an highly socially stimulating environment to the developing pup. Communal nest characterizes the natural ecologic niche of many rodent species including the mouse. At adulthood, CN reared mice, compared to mice reared in standard nesting laboratory condition (SN), show an increase in BDNF protein levels and longer survival of BrdU-positive cells in the hippocampus. Open field and elevated plus maze results indicate that CN mice, although showing levels of exploratory and locomotor activity similar to those of SN mice, displayed increased anxiety-like behavior, performing more thigmotaxis in the open field and spending less time in the open arms of the plus maze. Furthermore, CN mice displayed higher levels of immobility behavior in the forced swim test. Overall, these findings show that CN, an highly stimulating early social environment, increases adult neuronal plasticity, as suggested by high BDNF levels and augmented number of newly generated cells in the hippocampus, which is associated to an increased anxiety- and "depression"-like behavior. These findings are discussed in the framework of the neurotrophin hypothesis of depression.