Trophic factors

Bcl-x is a gene in the bcl-2 family that inhibits apoptosis after trophic factor deprivation in vitro. 

Another area where polymers are making a significant difference in nerve regeneration is the use of polymers to encapsulate and release trophic factors, or encapsulate cells that release nerve growth factor or other agents that enhance the regeneration process. This chapter details the advances in the use of polymeric biomaterials that have been explored for nerve regeneration in the peripheral and central nervous systems. 

Trophic factors can also be supplied through less specific mechanisms. Growth factors are synthesized by a wide variety of cell types, including neurons and glial cells. 

Individual neurons and glial cells are responsive to a number of different growth factors. Growth factors play both unique and overlapping roles in the development and sustenance of these cells. Perhaps the most dramatic example of this is the elaborate array of trophic factors that have evolved to support spinal motor neurons. There are presently at least 15 different factors that are known to influence the survival of these cells [4]. 

NGF also has actions within the CNS, although it is not particularly abundant in the CNS. Its synthesis appears to be largely restricted to the hippocampus and neocortex, and even in these regions it is present at relatively low concentrations relative to the other neurotrophins. The most prominent population of NGF-responsive neurons expressing TrkA are the basal forebrain cholinergic neurons. The principal projections of these neurons are to the hippocampus and cortex, which conforms with the concept that NGF acts as a target-derived trophic factor in the CNS, just as it does in the peripheral nervous system (PNS). NGF also acts on a subpopulation of cholinergic neurons within the striatum. These interneurons express the NGF receptor, TrkA, and respond to NGF. However, they do not appear to rely entirely on NGF for their survival, and the specific actions of NGF on this neuronal population have not been clearly defined. NGF may also have autocrine actions in the CNS, as some neuronal populations have been identified that express both TrkA and NGF. 

NGF has effects on the physiological responses of mature neurons. NGF acts as a target-derived trophic factor for pain neurons, which innervate peripheral tissues such as the skin. Inflammation of these peripheral tissues leads to local elevation of NGF synthesis and abundance. Elevated concentartions of NGF are responsible for the enhanced sensitivity to pain that accompanies inflammation. This is due to the ability of NGF to lower the sensory threshold of the pain fibers, leading to hyperalgesia. Nocioceptive sensory neurons mediating pain sensation are entirely dependent upon NGF for their survival as these cells are selectively lost in animal in which either the NGF or TrkA genes have been knocked out. These animals are insensitive to pain and live only a few weeks. 

The receptor for NGF is TrkA, a 140 kDa cell surface protein that specifically binds NGF, but not other neurotrophins [5, 6, 9]. TrkA is expressed on the neuronal cell body and on neuronal processes. In its action as a target-derived trophic factor, NGF is secreted within the target organ and it then binds to TrkA receptors present on the growing neuronal process or synapse. The NGF-TrkA complex is then internalized and subsequently translocated to the cell body by retrograde axonal transport. In those cells that respond to NGF through autocrine or paracrine mechanisms, the growth factor can bind to any of the widely distributed TrkA molecules on the neuronal membrane. 

NT4/5 is expressed in muscle and this neurotrophin can support facial motor neurons as well as other populations of motor neurons. Interestingly, NT4/5 expression is regulated by the activity of the muscle and this neurotrophin stimulates axonal sprouting, suggesting that it acts as a muscle-derived trophic factor for motor neurons. 

Cardiotrophin 1 acts as a survival factor for spinal motor neurons. CT-1 is synthesized by both skeletal muscle and myotubes and has been shown to be secreted from the latter, suggesting that it acts as a target-derived trophic factor. Indeed, in CT-1 knockout mice there is a loss of motor neurons in the spinal cord and brainstem [16]. CT-1 also promotes the survival of dopaminergic neurons and ciliary neurons. 

Persephin (PSPN) has been shown to promote the survival of basal forebrain neurons including both cholinergic neurons. Moreover, it supports midbrain dopaminergic neurons. PSPN is expressed in the striatum, consistent with its role as a target-derived trophic factor for these cells. 

Motor neurons provide a compelling example of how a single class of neurons can be supported by an extraordinarily wide range of factors. More than 15 growth factors have been shown in vitro or in vivo to sustain these cells. Some of these are derived from the muscle target, while others are elaborated by ensheathing Schwann cells and by cells resident within the spinal cord. It is likely that motor neurons rely upon multiple factors for their survival and different subpopulations of motor neurons may exhibit unique combinations of trophic factor dependence [4]. 

Retrograde transport returns trophic factors, exogenous material and old membrane constituents to the cell body 492... 

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