Neuronal death after trophic factor deprivation

Since the discovery of nerve growth factor (NGF) nearly 40 years ago, extensive studies have elaborated the trophic relationship between a neuron and its end organ. Much evidence has accumulated that depicts the crucial role of neurotrophic factors in determining neuronal survival both during development and after injury. The molecular events by which trophic factors determine whether an individual neuron lives or dies are poorly understood. The function of active protein synthesis as a prerequisite for neuronal death has led to the hypothesis that all neurons contain a mechanism to self- destruct or a phenomenon of programmed cell death. The loss of trophic support may, therefore, lead to the initiation of this so called 'suicide' program within individual cells. Recently, multiple other trophic factors have been discovered. At least two of these factors, brain-derived neurotrophic factor and neurotrophin-3, appear related to members of the same gene family as the prototypic neurotrophic factor, nerve growth factor. Other metabolic factors, such as intracellular calcium, may be instrumental in determining the dependence of individual neurons on specific trophic support. A 'set-point' hypothesis has been described concerning the relationship between intracellular calcium and the NGF dependency of embryonic neurons in cell culture. Changes in calcium metabolism may be an important determinant in altering trophic dependence and naturally occurring cell death. Neurotrophic factors also influence the reaction of the neuron to axotomy and subsequent axonal regeneration. Exogenously supplied trophic factors may prevent neuronal loss after axotomy when supplied at the site of injury. Both NGF and FGF have been shown to enhance early regeneration across gaps within silicone chambers. After axotomy, NGF and the NGF receptor are both increased in the Schwann cell within the distal nerve segment; such changes may be important in providing neurotropic support for growing axons. Understanding these neurotrophic agents may allow one to control better the fate of individual neurons during development or after injury. The ability to alter the neuronal response to injury and to trophic factor deprivation has potential clinical significance. By understanding mechanisms associated with neuronal death, one may gain insight into the causes of neurodegenerative disorders characterized by neuronal loss and develop possible therapeutic strategies to ameliorate neuronal loss. Any agent able to mitigate the disastrous sequelae after neuronal trauma may have clinical utility.