Overexpression of tumour necrosis factor alpha in the brain of transgenic mice differentially alters nerve growth factor levels and choline acetyltransferase activity.

Tumour necrosis factor alpha (TNF-alpha) is a pleiotrophic cytokine synthesized primarily by macrophages and monocytes, which exerts a variety of biological activities during inflammatory responses, immune reactions, and wound healing. Within the central nervous system (CNS), the basal levels of TNF-alpha are almost undetectable, but increase after neurological insults. Using transgenic mice expressing high levels of TNF-alpha in the CNS, we investigated the effect of this cytokine on the levels of brain nerve growth factor (NGF), a neurotrophin playing a crucial role in the development, maintenance and regeneration of basal forebrain cholinergic neurons. The immunoenzymatic assay and in situ hybridization revealed that the constitutive expression of NGF decreased in the hippocampus, increased in the hypothalamus, while remained unchanged in the cortex. Moreover, septal cholinergic neurons which receive trophic support from NGF produced in the hippocampus display loss of choline acetyltransferase immunoreactivity, suggesting that the reduced availability of NGF may influence negatively the synthesis of brain cholinergic neurons. These observations indicate that the basal level of brain NGF can be influenced negatively or positively by local expression of TNF-alpha and that this cytokine, through dose-dependent regulation of NGF synthesis and release, may be involved in neurodegenerative events associated with aging.

High-dose anabolic androgenic steroids modulate concentrations of nerve growth factor and expression of its low affinity receptor (p75-NGFr) in male rat brain.

The effects of treatment with a high dose of nandrolone or testosterone on nerve growth factor (NGF) levels and NGF low-affinity receptor (p75-NGFr) distribution in the brain were analyzed. Nandrolone, subcutaneously injected in rats for several weeks, caused an increase of NGF levels in the hippocampus and septum and a decrease in the hypothalamus. The number of p75-NGFr-immunoreactive neurons and the p75-NGFr expression levels were reduced in the septum and vertical and horizontal Broca's bands. Testosterone injections caused an increase of NGF levels in the hippocampus, septum, and occipital cortex and induced an upregulation of p75-NGFr in the forebrain NGF target regions. This testosterone effect suggests that nandrolone and testosterone affect brain NGF target cells by a different mechanism(s). Nandrolone may interfere with NGF transport and/or utilization by forebrain neurons, causing an altered p75-NGFr expression and NGF accumulation as a consequence. Since NGF is known to maintain forebrain neurons and to regulate neurobehavioral functions, including memory, learning, and defensive behavior, it is possible to hypothesize that this neurotrophin may play a role in the mechanism of action of anabolic androgenic steroids (AAS) in the brain and be associated with endocrine and behavioral dysfunctions occurring due to AAS abuse.

mRNA for NGF and p75 in the central nervous system of rats affected by experimental allergic encephalomyelitis.

In this study we measured the concentration of nerve growth factor (NGF) and the expression of NGF and the low affinity NGF-receptor (NGF-r) mRNA in the central nervous system (CNS) of rats affected by experimental allergic encephalomyelitis (EAE) during the acute phase of the disease. Significant levels of NGF protein were found in thalamus and cortex on day 13 post-immunization. Molecular analysis of the NGF gene expression and of its NGF-r revealed that they were enhanced in several regions of the CNS of EAE rats when compared with untreated animals. These results suggest a functional link between local NGF synthesis and this autoimmune inflammatory disease.

Monosodium glutamate increases NGF and NPY concentrations in rat hypothalamus and pituitary.

The effects of MSG treatment on NGF and NPY levels were analysed in the hypothalamus, pituitary, adrenal, thyroid and testis of adult rats. Daily i.v. injections of MSG (1 g kg-1 for 1 week) induced an increase of NGF in the hypothalamus (control (C) = 378 +/- 54; saline (S) = 369 +/- 36; MSG = 479 +/- 35 pg g-1 tissue; p < 0.001) and pituitary (C = 310 +/- 34; S = 376 +/- 114; MSG = 576 +/- 98 pg g-1 tissue; p < 0.01). Hypothalamic and pituitary NPY concentrations were also altered in the MSG-treated rats. Compared with saline-treated rats, the NPY concentration increased by 43% in the hypothalamus and 37.5% in the pituitary of MSG-treated rats. No significant changes in NGF and NPY content were found in the adrenal or thyroid of treated animals. These results suggest that hypothalamic and pituitary NGF and NPY levels may be involved in the control of neuroendocrine functions that are affected by MSG treatment.

Effect of NGF antibodies on mast cell distribution, histamine and substance P levels in the knee joint of TNF-arthritic transgenic mice.

We have previously shown an increase in nerve growth factor (NGF) levels and in mast cell (MC) distribution in the synovium of patients affected by rheumatoid arthritis. We now report that purified NGF antibodies injected into arthritic transgenic mice carrying the human tumour necrosis factor-alpha (TNF-alpha) gene caused reduction in the number of MCs, as well as a decrease in histamine and substance P levels within the synovium. These observations suggest that NGF antibody might be useful in studying the role of these pro-inflammatory markers in joint arthritis.

Schistosoma mansoni infection enhances the levels of NGF in the liver and hypothalamus of mice.

Schistosoma mansoni infection in adult mice is known to cause granulomas in the liver and intestine. Using a specific enzyme-linked immunoassay, it was found that Schistosoma mansoni infection enhances the level of nerve growth factor in the liver and surprisingly also in the hypothalamus. Exogenous administration of purified NGF antibodies inhibits NGF biological activity both in the hypothalamus and liver and drastically reduces the number of NGF-responsive cells, the mast cells, present in liver granuloma. These findings and those reported by others showing the effect of NGF on cells of the immune system support the hypothesis that this molecule plays a role in neuroendocrine-immune interactions.