The time course of nerve growth factor content in different neuropsychiatric diseases - a unifying hypothesis

Abstract

Nerve growth factor (NGF) is the prototype of related neurotrophic proteins, the so-called neurotrophins. NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system (PNS) as well as of the neurons in the cholinergic basal forebrain (CBF). In the mature peripheral and central nervous system (CNS) NGF is also biologically active; NGF facilitates neuronal plasticity and regulates synaptic transmission and connectivity. Besides this well established neurotrophic function, recent findings suggest a role of NGF in neuroimmune and stress-associated processes, which NGF imparts not only as the classical "target-derived messenger", that is retrogradely transported within NGF-sensitive neurons, but also as para- and autocrine cytokine modulating the function of non-neuronal cells. Since neurotrophins are produced in very small amounts in vivo, NGF-sensitive cells have to compete for the limited NGF even under physiological conditions, so that normally only less than 10% of NGF receptors (NGFR) are saturated with their endogenous ligand. Consequently, it is feasable that minute changes in NGF concentrations can influence neuronal function in an extensive way. Hence, one plausible pathomechanism of disease(s) may be that a deficiency in NGF leads to malfunction of NGF-sensitive neurons. The change in NGF concentrations in the course of several diseases, namely during alcoholic and diabetic neuropathy as well as in Alzheimer's disease (AD) and several lesion-models of the CBF, indicates that fluctuations of endogenous NGF concentrations in PNS and CNS follow a distinctive pattern. An initial deficit of NGF at the onset of pathological processes is typically followed by its temporary elevation, during which some neuronal deficits may be partially ameliorated. However, if the disease progresses a decrease of NGF is typically observed, which appears to be a "normalization" of formerly elevated NGF concentrations. In our hypothesis we postulate that after acute or chronic injuries NGF is up-regulated as an intrinsic attempt to regenerate NGF-sensitive neurons. After long-term exposure to noxious processes, however, this compensatory increase of NGF cannot be maintained and eventually breaks down. The extent of such a compensatory up-regulation may depend on age and condition of NGF-sensitive neurons as well as on the type of lesion (acute or chronic). Furthermore, we also postulate that an exceeding level of NGF or its chronic elevation could even be detrimental to neuronal functioning under certain conditions. Thus, endogenous NGF has the capacity to modulate and even to compensate different kinds of harmful processes and in this way it may reinstate the homeostatic equilibrium. In our view, it seems to be a more appropriate approach to regard NGF changes as independent of classical constructs of neuropsychiatric diseases. Perhaps our understanding of NGF may even model for a new approach to the aetiology of multifactorial neuropsychiatric disorders.

Phospholipase Cγ in Distinct Regions of the Ventral Tegmental Area Differentially Modulates Mood-Related Behaviors

“…More recently, these factors have been implicated as mediators of neuronal maintenance and plasticity in the adult nervous system (Barde, 1989;Lindsay et al, 1994;Patterson et al, 1996;Lu and Figurov, 1997). Neurotrophic factor levels are altered during aging and in models of neurodegeneration and neuropsychiatric disorders, whereas intracranial infusions of neurotrophic factors can have palliative effects in these models (Gash et al, 1996;Nestler et al, 1996;Duman et al, 1997;Hellweg et al, 1998;Smith et al, 1999).…”

Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: distinct converging pathways

“…Thus, evidence has suggested that impairments of these neurons may be due to a decreased action of NGF. However, there have been no conclusive reports of changes in NGF levels (Hellweg et al ., 1998a), suggesting that lack of neurotrophic support is likely also to involve NGF receptors and /or associated signalling events.…”

“…No matter what the associated molecular events are, some CNS neurons that are particularly affected in the aged or diseased brain require a constant supply of NGF throughout life (Perry, 1990;Hellweg et al ., 1998b;Gustilo et al ., 1999;Ha et al ., 1999). Thus, it is not unlikely that NGF promotes or maintains adequate levels of signalling cascades that are necessary to provide a healthy cellular homeostatic balance.…”

Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats

“…In mammals five different neurotrophins have been identified to date: the prototypical nerve growth factor (NGF), 3,4 brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3, -4 and -5. [5][6][7] There is strong evidence supporting the importance of the family of NGF-related neurotrophins in maintaining the function of mature neurons in the CNS [8][9][10] as neurotrophins are known to be critical for both growth and survival of neurons during development in vivo and in vitro. 3,5,6 Withdrawal of neurotrophins can lead to impaired neuronal function and even apoptotic death of adult neurons.…”

“…3,5,6 Withdrawal of neurotrophins can lead to impaired neuronal function and even apoptotic death of adult neurons. 9 Recent studies have elucidated the mechanisms that underlie neurotrophic inhibition of cell death, 11 including the mechanisms of regulation of both Bcl-2 and Bad, with one of the targets of this pathway being cAMP-response element binding protein CREB. 11,12 The NT hypothesis proposes that repetitive neuronal activity enhances the expression, secretion and/or actions of NTs at the synapse to modify synaptic transmission and connectivity and thus provides a connection between neuronal activity and synaptic plasticity.…”