Stress and nerve growth factor: Findings in animal models and humans

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Abstract

Stress is elicited by environmental, social or pathological conditions occurring during the life of animals and humans that determine changes in the nervous, endocrine and immune systems. In the present review, we present data supporting the hypothesis that stress-related events both in animal models and humans are characterized by modifications of endogenous nerve growth factor (NGF) synthesis and/or utilization. Stress inducing alteration in NGF synthesis and/or utilization appears to be more severe during neurogenesis and in early postnatal life. However, NGF endogenously released during stress may promote remodeling of damaged tissues following acute and/or chronic stressful events.

Section snippets

Stress

Stress is triggered by numerous unexpected environmental stimuli occurring during life, such as aggressive behavior, fear, forced physical activity, sudden environmental changes, social isolation or pathological situations Denenberg et al., 1964, Greenough and Volkmar, 1973, Hilakivi-Clarke et al., 1991, McEwen and Sapolsky, 1995, Mohammed et al., 1990, Mohammed et al., 1993, Weiner, 1989. Considerable evidence published in the last decades has focused on a constellation of neurochemical,

NGF

NGF is the first discovered and best characterized member of a family of neurotrophic factors collectively called neurotrophins, which include brain-derived neurotrophic factor (BDNF) and neurotrophins 3 and 5 (NT-3, NT-5) (Barde, 1990). The term NGF was introduced to describe a growing effect on the developing sensory and sympathetic neurons of birds and mammals Levi-Montalcini, 1987, Levi-Montalcini and Angeletti, 1966, Levi-Montalcini and Angeletti, 1968, Levi-Montalcini et al., 1990,

NGF and hormones

Biochemical, pharmacological and structural studies have revealed that NGF is synthesized in the granular convoluted tubules of the mouse male SG soon after puberty and that the female SG produces less NGF than the males Levi-Montalcini, 1987, Levi-Montalcini and Angeletti, 1968. Exogenous administration of testosterone to young or adult females enhances the synthesis of NGF in the SG, whereas castration in males drastically reduces the SG NGF levels (Levi-Montalcini and Angeletti, 1968).

NGF and cytokines

Cytokines are produced not only by cells of the immune system, but also by cells localized within the CNS. They are generally associated with immune and inflammatory responses and participate in a variety of immunological and neuroimmunological disorders. There is also evidence showing that cytokines are involved in promoting repair of damaged brain and spinal cord neurons. For example, cytokines such as tumor necrosis factor (TNF-α) and some interleukins (IL-1, IL-6) can be produced in the

Stress and NGF

The observation that stress can produce significant alterations in circulating NGF levels raised the question as to whether prolonged exposure to high release of endogenous NGF and corticosteroids may elicit production of NGF antibodies. To address the question of whether chronic stressful conditions affect long-lasting neuroimmune interaction, we tested the effect of the endogenous released NGF on the immune responses. Using an NGF-deprived animal model (Johnson et al., 1993), we found that in

NGF in arousal–sedation conditions

Repeated experiences of defeat and submission significantly enhance the level of NGF compared with the dominant, attacking male mouse (Maestripieri et al., 1990). The increased amount of NGF values in subordinate mice does not correlate with either the number of attacks received or the defensive reactions opposed to them, suggesting that other stimuli, e.g., of a psychological nature, are implicated in the mechanisms triggering the NGF release (Maestripieri et al., 1990). The results of these

NGF and stress-related events in humans

Following up the observations on stress responses and neurotrophin release in animal models and in humans, our studies were extended to human behavioral deficits. It was hypothesized that aggressive behavior and stress induced by maternal separation or delivery causing significant alteration of basal NGF levels Aloe et al., 1986, Aloe et al., 1994c, Cirulli et al., 1998, Luppi et al., 1993, Manni et al., 1998 or causing changes in neurotrophic factor during a critical developmental stage of

Concluding remarks

There is now considerable experimental evidence to demonstrate that stress and stress-related events, via a complex network of multidirectional signals involving the nervous, endocrine and immune systems, can influence the production of important biological mediators, including neurotrophins. It is known, for example, that exposure to acute or chronic stress, regardless of age Hadjiconstantinou et al., 2001, Mohammed et al., 1993, can lead to significant alteration of circulating and brain NGF

Acknowledgements

This study was supported by an Italian Space Agency (ASI) grant, ASI-ARS-98-45, and by PF ISS Danno Cerebrale Ipossico-Ischemico nel Neonato.

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