Environmental enrichment-behavior-oxidative stress interactions in the aged rat: issues for a therapeutic approach in human aging.

The effects of environment enrichment on motor activity, exploration, and cognitive performances were studied in aged rats. Both nonimpaired (NI) and impaired (I) rats were submitted to daily training in a complex-enriched environment (cEE) for 60 days. Animals were examined at spatial water maze task, passive avoidance test, open-field test, and sensorimotor coordination tasks (bridges test and Marshall scales). At the end of experiments, animals were killed for brain biochemical determinations (gluthatione content and specific-ChAT activity). Results after the first evaluation (before training) corroborate that the aged rat population showed a heterogeneity in behavioral patterns like that observed in humans. Also, cEE modified exploration activity, cognition, motor functions, and biochemical markers in both NI and I groups, but changes reached significant relevance for the last group. It is significant that neurotrophins, "novo" synthesis of neurotransmitters, and oxidative stress levels may mediate the observed changes, indicating that the aged brain still has appreciable plasticity in response to well-manipulated environmental stimulation. Finally, our results also support the novel concepts and programs in prevention/reduction both in incidence/severity and outcome of age-associated neurodegenerative conditions.

[Changes in nerve growth factor levels related to age and neurotrophic treatment in non-human primate]. / Cambios en los niveles de factor de crecimiento nervioso con el envejecimiento y el tratamiento neurotrófico en primates no humanos.

INTRODUCTION: To examine the amounts and role of growth factors in different tissues and corporal fluid, new sensitive techniques have to be developed. A major problem is that the normal concentration of trophic substances, such as nerve growth factor (NGF), in central and peripheral nervous system and in fluids is very low (ng pg/ml). A valuable method of research is the sensitive two site enzyme immunoassay using the monoclonal antibody 27/21 to mouse NGF. Materials and methods. The present work applied this enzyme immunoassay to examine the NGF levels in normal non human primate sera (n= 94) and applied this assay to study of NGF levels in two non human primate receiving NGF infusion: one young and one aged. Two groups of non human primate sera were studied one young adult (n= 69) and one aged (n= 25). The serum samples NGF treated non human primate were taken before the infusion and at the 1st week and 1st, 3rd, 6th and 12th month after infusion. RESULTS: To further test the specificity of conjugate binding, dilutions of the non human primate sera were preincubated with an excess of monoclonal NGF antibody 27/21 in solution. With this strategy it was possible to completely block the signal obtained using the enzyme immunoassay. We found very low levels of NGF in aged monkeys (0.054 ng/ml) when compared with young adult group (0.152 ng/ml) (p> 0.01). The NGF levels in aged non human primate treatment with NGF was very low before (0.50 ng/ml) and during NGF treatment evolution time, whereas at the the 12th month showed an increase in NGF levels (0.180 ng/ml). We found normal values of NGF in the young monkey before and during the first year after NGF infusion. CONCLUSIONS: Using the enzyme immunoassay described it is possible to know the serum concentration of NGF immunoreactive in non human primate and this assay is able to detect peripheral changes in NGF levels after intracerebral infusion of NGF.

[Evoked potentials in the sacred baboon: long-term follow-up of intracerebroventricular infusion of nerve growth factor]. / Potenciales evocados en el babuino sagrado: seguimiento a largo plazo de la infusión intracerebroventricular de factor de crecimiento nervioso.

INTRODUCTION AND OBJECTIVE: It is well known that in aged animals cognitive deficit occurs, homologous with that occurring in Alzheimer's disease in humans, and as has been shown in others species, this may be attenuated by administration of nerve growth factor (NGF). Therefore the basic aim of this study was to make an electrophysiological evaluation of the repercussion that there might be after long-term administration of this neurotropin in the sacred baboon (Papio hamadryas) comparing aged with young animals. MATERIAL AND METHODS: We studied a six year old male and a 39 year old female, after sedation. Long-term intraventricular administration of NGF was carried out using a continuous infusion pump, at a dose of 2.1 micrograms/kg/day. Recordings were made before installing the pump and 1, 3 and 6 months after insertion. A Neuropack Four-mini set for evoked potentials (Nihon Kohden) was used to record auditory evoked potentials from the brain stem and visual evoked potentials due to flash. RESULTS AND CONCLUSION: In both animals there were modifications of their electrophysiological responses. These reached a maximum after one month, more markedly in the older animal and this could possibly be related to the neuromodulator effect of NGF.

[Obtention and characterization of murine beta-NGF. Application in a model of cerebral aging]. / Obtención y caracterización del beta-NGF murino. Aplicación en un modelo de envejecimiento cerebral.

INTRODUCTION: beta-NGF is a basic protein of 118 aminoacids which acts are a trophic factor for sensory and sympathetic neurons of the peripheral nervous system, and on cholinergic neurons of the anterior basal cerebrum. OBJECTIVES: In view of the functional effect of beta-HGF and its possibilities as a therapeutic agent in neurodegenerative disease, including Alzheimer's disease in this study our aim was to obtain, characterize and show the main results of the application of beta-NGFm in a model of cerebral ageing in rats with cognitive disorders. MATERIAL AND METHODS: For the obtention of beta-NGFm we followed Mobley's method as modified by Ebendal and used mouse submaxillary gland as a source of raw material. The characterization studies were carried out by application of seven techniques which allowed physicochemical characterization and demonstration of the biological activity of the product. Application of beta-NGF obtained under these conditions was carried out in a mode of cerebral ageing and the effects of treatment were assessed by conduct studies, measurement of the activity of the enzyme acetyl cholinesterase and study of neural plasticity. CONCLUSIONS: Characterization studies carried out on the beta-NGFm showed that the protein obtained consists of a mixture of molecules of beta-NGFm which are intact at their extreme N-Terminal, and molecules which have lost the octapeptide of the N-terminal position and show some modification increasing hydrophobicity. All these species were recognized immunologically by the specific antibody anti-NGFm and showed biological activity.

Nerve growth factor improves evoked potentials and long-term potentiation in the dentate gyrus of presenile rats.

Chronic infusion of nerve growth factor (NGF, 1.2 microg/day) for 14 days to presenile rats (17 months at the beginning of treatment) that showed an initial cognitive impairment led to an improved long-term potentiation in the dentate gyrus. Both the relative increase of the slope of the population excitatory postsynaptic potential and that of the population spike were enhanced by NGF pretreatment after long-term potentiation induction at 400 Hz. The treatment was also able to increase the diminished baseline amplitude of the population spike, an effect not seen when the treatment was applied to older animals [Bergado, J., Fernández, C.I., Gómez-Soria, A., González, O., 1997a. Chronic intraventricular infusion with NGF improves LTP in old cognitively-impaired rats. Brain Res. 770, 1-9] stressing the importance of an early start of trophic therapy to achieve better results.

Chronic intraventricular infusion with NGF improves LTP in old cognitively-impaired rats.

Aged (21 months) cognitively-impaired male Sprague-Dawley rats received intraventricular infusion of nerve growth factor (NGF) or cytochrome C (Cit C) for 14 or 28 days using miniosmotic pumps and were evaluated either 1 week or 3 months after treatment. Groups of untreated young, aged-impaired and aged non-impaired rats were also evaluated. Under narcose recording and stimulating electrodes were stereotactically implanted in the dentate gyrus and the perforant path. The stimulation intensity was individually adjusted to obtain a half-maximal population spike (P) for test stimuli and a quarter-maximal for tetanization. The amplitude and latency of P and the slope (S) of the field EPSP were determined before and at 2, 5, 15, 30 and 60 min after tetanization at 400 Hz. Paired stimuli at 30 ms interval were also applied before and after tetanization. Aged, cognitively impaired rats showed an absent S potentiation and a delayed P potentiation, both in amplitude and latency, while non-impaired rats behaved like the young controls. Paired pulse inhibition showed no difference among groups before or after tetanization suggesting that the impaired potentiation is not due to an increased retroactive inhibition. NGF treatment ameliorates LTP deficits to levels equivalent to non-impaired rats, while Cit C controls showed no improvement. No differences appear among NGF treated groups, but evidence suggest that the animals evaluated 3 months after treatment developed a stronger potentiation.

Toxicidad neuronal de la interleucina-2 recombinante humana en ratas: validación morfoconductual / Neuronal toxicity of human recombinant interleukin 2 in rats: morphoconductual validation

Introducción y objetivo. La afectación de memoria que se observa en el envejecimiento es una manifestación de la disminución de las funciones cognitivas con la edad, la cual está estrechamente asociada a cambios neuropatológicos y bioquímicos en áreas colinérgicas del sistema nervioso central (SNC). Las citoquinas, descritas por primera vez como moléculas inmunoreguladoras, están también implicadas en reacciones defensivas del cerebro. Estudios relacionados con la acción de la IL-2 sobre el SNC le atribuyen un efecto bloqueador sobre la secreción de acetilcolina a nivel hipocampal. Material y métodos. Hemos desarrollado un estudio dirigido a caracterizar los efectos neurotóxicos centrales de esta citoquina mediante la infusión crónica intraperitoneal de IL-2 recombinante humana (IL-2rh) en ratas jóvenes y viejas de la línea Sprague Dawley. Resultados y conclusiones. Los resultados obtenidos, aunque parciales, no parecen referir el posible efecto in vivo de la IL-2 sobre la función colinérgica central, pero si son consistentes con la implicación probable de esta citoquina en el deterioro cognitivo senescente y, de manera particular, en el deterioro de la memoria espacial asociada a la edad y/o en el curso de trastornos neurodegenerativos relacionados

Effects of chronic infusion of nerve growth factor (NGF) in rats with nucleus basalis magnocellularis lesion.

We attempted to evaluate the effects of bilateral injection of ibotenic acid (IA) into the nucleus basalis magnocellularis (nbm) of rats as well as the potential recovery mediated by the infusion of nerve growth factor (NGF). The lesion caused an impairment of learning and memory processes. Also, a severe depletion of choline acetyl transferase activity was detected in cortical areas. After the NGF administration, a significant reversion of these functional changes was observed. Thus, IA-lesioned rats might serve as a model for the evaluation of neurotrophic factors actions on basal forebrain damaged neurons.

Effects of chronic infusion of nerve growth factor (NGF) in AF64A-lesioned rats.

We report here the behavioral and biochemical recovery induced by the nerve growth factor (NGF) administration in AF64A-treated rats. Retention in the passive avoidance test was affected by lesion but it was significantly improved after the NGF treatment. Similar results were observed in the performance during the Morris water maze (MWM) task. Remarkable losses in the ChAT activity were detected in some brain regions from lesioned rats. The NGF-induced alleviation of choline acetyltransferase (ChAT) activity losses and cognitive functions suggest a trophic and protective action on the remaining cholinergic neurons after the lesion. Thus NGF therapy could be considered as a possibility mainly in the early course of Alzheimer disease.

Effects of chronic infusion of nerve growth factor (NGF) in rats with nucleus basalis magnocellularis lesion

We attempted to evaluate the effects of bilaeral injection of ibotenic acid (IA) into the nucleus basalis magnocelluraris (rbm) of rats as well as the potential recovery mediated by the infusion of nerve growth factor (NGF). The lesion caused and impairment of learning and memory processes. Also, a severe depletion of choline acetyl transferase activity was detected in cortical areas. After the NGF administration, a significant reversion of these functional changes was observed. Thus, IA-lesioned rats might serve as a model for the evaluation of neurotrophic factors actions on basal forebrain damaged neurons

Effects of chronic infusion of nerve growth factor (NGF) in AF64A-lesioned rats

We report here the behavioral and biochemical recovery induced by the nerve growth factor (NGF) administration in AF64A-treated rats. Retention in the passive avoidance test was affected by lesion but it was significantly improved after the NGF treatment. Similar resultas were observed in the performance during the Morris water maze (MWM) task. Remarkable losses in the ChAT activity were detected in some brain regions from lesioned rats. The NGF-induced alleviation of choline acetyl transferase (ChAT) activity losses and cognitive functions suggest a trophic and protective action on the remaining cholinergic neurons after the lesion. Thus NGF therapy could be considered as a possibility mainly in the early course of Alzheimer disease

Neurorestorative techniques as experimental approach to Alzheimer disease treatment

Laboratory animals have been used to reproduce some structural changes and/or memory impairment observed in Alzheimer disease by means of specific lesions or using old animals (Kordower and Gash, 1986). Different sources and places for the neural graft have been reported showing the graft's ability to attain an adequate and specific innervation of the target as well as the behavioral recovery (Dunnett, 1991; Gage and Chen, 1992). Similar experimental procedures have been used to evaluate effects of exogenous nerve growth factor (NGF) infusion, whose influence on central cholinergic neurons is well documented (Gage et al. 1991; Pepeu et al., 1993)