Hellweg R, von Richthofen S, Anders D, Baethge C, Röpke S, Hartung H D, Gericke C A
Department of Psychiatry, Free University of Berlin, Federal Republic of Germany.
J Neural Transm (Vienna). 1998;105(8-9):871-903. doi: 10.1007/s007020050100.
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.
神经生长因子（NGF）是相关神经营养蛋白（即所谓的神经营养因子）的原型。NGF对于外周神经系统（PNS）中交感神经和神经嵴衍生的感觉神经元以及胆碱能基底前脑（CBF）中的神经元的正常发育至关重要。在成熟的外周和中枢神经系统（CNS）中，NGF也具有生物活性；NGF促进神经元可塑性并调节突触传递和连接性。除了这种已确立的神经营养功能外，最近的研究结果表明NGF在神经免疫和应激相关过程中发挥作用，NGF不仅作为经典的“靶源性信使”（即在NGF敏感神经元内逆行运输）发挥作用，还作为旁分泌和自分泌细胞因子调节非神经元细胞的功能。由于神经营养因子在体内的产生量非常少，即使在生理条件下，NGF敏感细胞也必须竞争有限的NGF，因此通常只有不到10%的NGF受体（NGFR）被其内源性配体饱和。因此，NGF浓度的微小变化可能会广泛影响神经元功能是可行的。因此，一种合理的疾病发病机制可能是NGF缺乏导致NGF敏感神经元功能障碍。在几种疾病过程中，即酒精性和糖尿病性神经病变以及阿尔茨海默病（AD）和CBF的几种损伤模型中，NGF浓度的变化表明PNS和CNS中内源性NGF浓度的波动遵循独特的模式。在病理过程开始时NGF最初缺乏，随后通常会暂时升高，在此期间一些神经元缺陷可能会部分改善。然而，如果疾病进展，通常会观察到NGF下降，这似乎是先前升高的NGF浓度的“正常化”。在我们的假设中，我们推测在急性或慢性损伤后，NGF会上调，这是一种内在的尝试，旨在使NGF敏感神经元再生。然而，在长期暴露于有害过程后，这种NGF的代偿性增加无法维持，最终会崩溃。这种代偿性上调的程度可能取决于NGF敏感神经元的年龄和状况以及损伤类型（急性或慢性）。此外，我们还推测，在某些情况下，NGF水平过高或其长期升高甚至可能对神经元功能有害。因此，内源性NGF有能力调节甚至补偿不同类型的有害过程，并以此方式恢复体内平衡。在我们看来，将NGF变化视为独立于神经精神疾病的经典概念似乎是一种更合适的方法。也许我们对NGF的理解甚至可以为多因素神经精神疾病的病因学提供一种新的研究方法。
