ENDOGENOUS NEUROPROTECTION FACTORS AND TRAUMATIC BRAIN INJURY - MECHANISMS OF ACTION AND IMPLICATIONS FOR THERAPY

Throughout evolution the brain has acquired elegant strategies to prot ect itself against a variety of environmental insults. Prominent among these are signals released from injured cells that are capable of ini tiating a cascade of events in neurons and glia designed to prevent fu rther damage. Recent research has identified a remarkably large number of neuroprotection factors (NPFs), whose expression is increased in r esponse to brain injury. Examples include the neurotrophins (NGF, NT-3 , NT-5, and BDNF), bFGF, IGFs, TGFs, TNFs and secreted forms of the be ta-amyloid precursor protein. Animal and cell culture studies have sho wn that NPFs can attenuate neuronal injury initiated by insults believ ed to be relevant to the pathophysiology of traumatic brain injury (TB I) including excitotoxins, ischemia, and free radicals. Studies of the mechanism of action of these NPFs indicate that they enhance cellular systems involved in maintenance of Ca2+ homeostasis and free radical metabolism. Recent work has identified several low-molecular-weight li pophilic compounds that appear to mimic the action of NPFs by activati ng signal transduction cascades involving tyrosine phosphorylation. Su ch compounds, alone or in combination with antioxidants and calcium-st abilizing agents, have proved beneficial in animal studies of ischemic brain injury and provide opportunities for development of preventativ e/therapeutic approaches for TBI.