Neurotrophic Factors in Central Nervous System Trauma

Although regeneration of injured neurons does not occur after trauma in the central nervous system (CNS), there is often significant recovery of functional capacity with time. Little is currently known about the molecular basis for such recovery, but the increased trophic activity in injured CNS tissue and the known properties of neurotrophic factors in neuronal growth and maintenance suggest that these polypeptides are probably involved in recovery of function. Members of the neurotrophin family, including nerve growth factor (NGF), brain-derived neurotrophic factors (BDNF), and neurotrophin 3 (NT-3), are capable of supporting survival of injured CNS neurons both in vitro and in vivo. They also stimulate neurite outgrowth, needed for reorganization of the injured CNS, and the expression of key enzymes for neurotransmitter synthesis that may need to be upregulated to compensate for reduced innervation. The effects of the neurotrophins are mediated through specific high affinity trk receptors (trk A, B, C) as well as a common low affinity receptor designated p75^NGFR. Another class of neurotrophic polypeptides also provides candidate recovery-promoting molecules, the heparin-binding growth factors' acidic and basic fibroblast growth factor (aFGF, bFGF). FGFs not only sustain survival of injured neurons but also stimulate revascularization and certain glial responses to injury. Both the neurotrophins and the FGFs, as well as their respective receptors, have been shown to be upregulated after experimental CNS injury. Further, administration of neurotrophins or FGF has been shown to reduce the effects of experimental injury induced by axotomy, excitotoxins, and certain other neurotoxins. The cellular basis for the potential therapeutic use of neurotrophic molecules is discussed as well as new strategies to increase neurotrophic activity after CNS trauma based on the recently obtained information on pharmacological and molecular control of the expression of these genes.

Key words: bFGF; neurotrophic therapy; neurotrophic factor expression; NGF; p75NGFR; spinal cord injury; trk