Brain Nerve Growth Factor Levels Research Articles

GM6 Attenuates Alzheimer's Disease Pathology in APP Mice.

Alzheimer's disease (AD) results in the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. Regardless of whether or not these entities are a cause or consequence of the disease process, preventing their accumulation or accelerating their clearance may slow the rate of AD onset. Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a six-amino-acid component of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected the accumulation of Aβ peptide and related pathologic changes (e.g., inflammation, nerve growth factor (NGF) expression, cathepsin B, and memory impairment). Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of inflammation and amyloid load, increased cathepsin B expression, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by ∼ 50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways at an early stage to slow the histological and clinical progression of AD.

NGF, brain and behavioral plasticity.

Nerve Growth Factor (NGF) was initially studied for its role as a key player in the regulation of peripheral innervations. However, the successive finding of its release in the bloodstream of male mice following aggressive encounters and its presence in the central nervous system led to the hypothesis that variations in brain NGF levels, caused by psychosocial stressor, and the related alterations in emotionality, could be functional to the development of proper strategies to cope with the stressor itself and thus to survive. Years later this vision is still relevant, and the body of evidence on the role of NGF has been strengthened and expanded from trophic factor playing a role in brain growth and differentiation to a much more complex messenger, involved in psychoneuroendocrine plasticity.

Involvement of the neurotrophin and cannabinoid systems in the mechanisms of action of neurokinin receptor antagonists

The anxiolytic- and antidepressant-like effects of the neurokinin (NK) receptor antagonists have been shown in behavioral studies. According to the involvement of neurotrophin signaling in the mechanisms of action of psychotropic agents, we aimed to investigate whether the selective NK1, NK2, or NK3 receptor antagonists (GR-205171, SR48968, and SR142801, respectively) affect nerve growth factor (NGF) contents in the brain regions involved in the modulation of emotions. To gain a mechanistical insight into the process by which the NK antagonists regulate brain NGF levels, we evaluated the role of the cannabinoid system which is linked to depression and/or antidepressant effects and appears to interact with neurotrophin signaling. According to the results, single injection of the NK receptor antagonists (3, 5, and 10mg/kg, i.p.) into gerbils did not alter NGF or endocannabinoid (eCB) levels quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. Three-week administration of 10mg/kg NK antagonists significantly elevated both NGF and eCB levels in brain-region specific fashion. Pre-application of the CB1 receptor neutral antagonist AM4113 (5.6mg/kg) prevented the elevation of NGF or eCB induced by the NK antagonists. AM4113 showed no effect by itself. We conclude that the cannabinoid system is implicated in the mechanisms of action of NK receptor antagonists including the upregulation of brain NGF levels.

The cannabinergic system is implicated in the upregulation of central NGF protein by psychotropic drugs

Studies on the regulation of nerve growth factor (NGF) levels by psychotropics are limited in scope and the mechanism(s) remain elusive which merit further elucidation. We aimed to perform a more comprehensive investigation on the possible effects of pharmacologically heterogeneous groups of psychotropic drugs on NGF contents in the brain regions involved in the modulation of emotions. As a mechanistic approach, we looked at the role of the cannabinergic system which is linked to depression and/or antidepressant effect and appears to interact with neurotrophin signaling. Following psychotropic treatment, NGF or endocannabinoid (eCB) contents were quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. In case of any significant change, the effects of pretreatment with the CB(1) receptor neutral antagonist AM4113 were investigated. Single injection of nortriptyline, isocarboxazid, citalopram, diazepam, risperidone (2.5, 5, and 10 mg/kg, each), and fluphenazine (0.25, 0.5, and 1 mg/kg) into rats did not alter NGF or eCB contents. Following 4-week treatment, all drugs except diazepam elevated NGF or eCB levels in dose-dependent and brain region-specific fashion. Pretreatment with the highest dose of AM4113 (5.6 mg/kg) prevented psychotropic-induced NGF or eCB elevation. AM4113 had no effect by itself. The cannabinergic system is implicated in the mechanisms of action of certain psychotropic drugs including the upregulation of brain NGF levels. This provides a better understanding of the pathophysiological mechanisms underlying neuropsychiatric disorders, leading to novel drug design.

Inhalation of Low-Level Formaldehyde Enhances Nerve Growth Factor Production in the Hippocampus of Mice

Objective: The effects of low-level formaldehyde (FA) inhalation on the amount of nerve growth factor (NGF) in the hippocampus of immunized mice were studied. Methods: Evaluation of NGF in the hippocampus was performed by ELISA and RT-PCR. Results: Exposure to 80 and 400 ppb FA significantly increased the brain NGF levels in the immunized mice. Evaluation of the NGF levels in the hippocampus of immunized mice showed that 400 ppb FA significantly increased the NGF content. The RT-PCR evaluation also showed higher concentrations of hippocampal NGF mRNA in the mice exposed to 80 and 400 ppb FA with immunization. Conclusion: Exposure of immunized mice to low levels of FA significantly increases NGF levels in the hippocampus.

Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year

This study examined the effects of long-term differential rearing on levels of brain nerve growth factor, its receptors, and their relationships to cognitive function. Adult rats (two months old) were placed into either enriched or standard housing conditions where they remained for 12 months. Animals from the enriched condition group had significantly higher levels of nerve growth factor in hippocampus, visual and entorhinal cortices compared with animals housed in isolated condition. Immunohistochemical analysis of brain tissue from the medial septal area revealed higher staining intensity and fibre density with both the low-affinity and the high-affinity nerve growth factor receptors. Enriched rats performed better than isolated rats in acquisition of spatial learning and had lower locomotion scores in the open field. These results provide further evidence that experimental stimulation results in increased production of trophic factors and structural reorganization in specific brain regions known to be involved in cognitive function.

Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits

It has been hypothesized that a deleterious key contribution to schizophrenia (SZ) development is a failure of migration and setting of young neurons into their appropriate cortical target sites, particularly in the entorhinal cortex (EC). To test this hypothesis in an animal model, we injected, in pregnant rats, on gestational day (GD) 9, or 10, or 11, or 12, the antimitotic compound methylazoxymethanolacetate (MAM) known to cause EC neuronal loss. We investigated whether or not EC disruption during prenatal development is able to affect behavior, including memory and learning, and brain nerve growth factor (NGF). Prenatally MAM treated young rats didn’t display gross behavioral changes in social interaction, open-field and novel object investigation tests. By contrast, GD11 and GD12 MAM treated rats had a retardation in passive avoidance acquisition, while, in GD12 animals, pain sensitivity was reduced. GD12 animals also showed increased NGF in the EC and remaining cortex. MAM treated animals showed no changes in paw NGF or substance P levels suggesting that the altered nociceptive response is not related to local downregulation of these two molecules. The possibility that these behavioral and biochemical alterations might be associated with the onset of SZ is discussed.

Chronic parasite infection in mice induces brain granulomas and differentially alters brain nerve growth factor levels and thermal responses in paws.

Schistosoma mansoni infection, both in humans and in animal models, is known to induce granulomas in the liver and intestine. It has also been reported that in humans the eggs of this parasite can reach the brain, causing psychiatric and neuropathological disorders. Whether this also occurs in rodents is unknown. To answer this question, mice were infected with this parasite and the central nervous system (CNS) examined at various time intervals. The results show that schistosomiasis induced granulomas in several regions of the CNS and increased nerve growth factor (NGF) levels in the cortex, hypothalamus and brain stem, but not in the hippocampus. The infection also caused paw hyperalgesia, as determined by the hot-plate test, and a local increase in NGF, but not in substance P. These findings indicate that the murine model of infection can be used for studying mechanisms leading to human neuroschistosomiasis and suggest that the neuropathological disorders and the sensory deficits observed in human schistosomiasis are associated with impaired levels of NGF in the peripheral and central nervous system.

Modification of lymphoid and brain nerve growth factor levels in systemic lupus erythematosus mice

In the present work we investigated the production of nerve growth factor (NGF) in the brain and peripheral tissues of female NZB/W F1 mice, a well characterized model of murine lupus. Our results indicate that while no significant difference in the NGF content was observed in the sera and tissues of NZB/W mice and its parental strains during the first months of life, the levels of circulating NGF and the NGF content in the kidneys significantly increase in the autoimmune mice during the development of the disease. The NGF-producing brain regions showed a decrease in NGF concentration in 8 month-old NZB/W mice. Moreover, we found a modification of the NGF concentration in the spleens of autoimmune mice at 5 and 8 months. Our data support the hypothesis of a correlation between NGF and the inflammatory state of systemic lupus erythematosus (SLE) and indicate that NGF could have a role in the pathogenesis of this disease.

Nerve growth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory impairments

Nerve growth factor (NGF) and choline acetyltransferase (ChAT) activity levels were measured in 7 different brain regions in young (3-month-old) and aged (2-years-old) female Sprague-Dawley rats. Prior to analysis the spatial learning ability of the aged rats was assessed in the Morris' water maze test. In the aged rats a significant, 15–30%, increase in NGF levels was observed in 4 regions (septum, cortex, olfactory bulb and cerebellum), whereas the levels in hippocampus, striatum and the brainstem were similar to those of the young rats. The NGF changes did not correlate with the behavioral performance within the aged group. Minor 15–30%, changes in ChAT activity were observed in striatum, brainstem and cerebellum, but these changes did not correlate with the changes in NGF levels in any region. The results indicate that brain NGF levels are maintained at a normal or supranormal levels in rats with severe learning and memory impairments. Ther results, therefore, do not support the view that the marked atrophy and cell loss in the forebrain cholinergic system that is known to occur in the behaviorally impaired aged rats is caused by a reduced availability of NGF in the cholinergic target areas. The results also indicate that the slightly increased levels of NGF are not sufficient to prevent the age-dependent atrophy of cholinergic neurons, although they might be important for the stimulation of compensatory functional changes in a situation where the system is undergoing progressive degeneration.

Ontogenesis of nerve growth factor and epidermal growth factor in submaxillary glands and nerve growth factor in brains of immature male mice: correlation with ontogenesis of serum levels of thyroid hormones.

Summary: Using specific and sensitive radioimmunoassays for nerve growth factor (NGF) and epidermal growth factor (EGF), we studied the developmental profile of NGF and EGF concentrations in male mouse submaxillary gland (SMG) from 2–60 days of age. We measured NGF concentrations in mouse cerebellum, cerebral cortex, and brain stem from ages 2–32 days. In addition, we assessed mouse serum thyroxine (T4) and triiodothyronine (T3) levels in seperate groups of animals ranging from 5–50 days of age. Mean SMG EGF content and concentration exceeded that of NGF between 2 and 18 days of age. At all subsequent ages, however, mean NGF and EGF content and concentration were similar. SMG NGF and EGF content were low at 2 days of age, decreased slightly through 8 days of age, and increased exponentially after 11 days of age with three phases of increase being apparent for both proteins. In the first phase, mean SMG NGF and EGF contents increased 2.4− and 2.3-fold respectively between 11 and 18 days of age. A second phase of increase was noted between 18 and 32 days when NGF and EGF increased 9845− and 7805-fold respectively. In phase three (32–60 days of age) more modest increases of 6.5-fold in mean NGF and EGF content were noted.Cerebellar NGF concentrations increased from 681 to 2241 pg/mg protein between ages 2 and 15 days and subsequently fell to a plateau level of 1304 pg/mg protein by age 18 days. Cerebral cortical NGF concentrations increased steadily from 251 to 1383 pg/mg protein between ages 2 and 32 days, whereas brain stem NGF concentrations maintained a plateau averaging 1100 pg/mg protein.Serum T4 concentrations in the mouse increased dramatically from 2.5 μg/dl at 5 days to a maximum of 8.1 μ/dl at 15 days, thereafter decreasing to a nadir 4.4 μ/dl by 40 days. Serum T3 concentrations followed a similar pattern, rising from 25 ng/dl on postnatal day 5 to 93 ng/dl on day 15, with a subsequent decline to 63 ng/dl by day 30. These results indicate a correlation between the increase in serum thyroid hormone levels in the mouse and the increases in SMG NGF and EGF levels and brain NGF levels between 5 and 32 days.Speculation: We and others have demonstrated that thyroid hormones increase brain NGF concentrations and stimulate submaxillary gland NGF and EGF synthesis. The present results are compatible with the hypothesis that the early increase in circulating thyroid hormone concentrations in the mouse play an important role in the increase in cerebral and cerebellar NGF levels during the first 3 wk and the increase in SMG NGF and EGF concentrations between 11 and 32 days of age. The known increase in mouse serum testosterone to adult male levels between 4–12 wk of age may be a factor in the late increase in NGF and EGF elevations after 32 days of age.