Neurotrophin-mediated potentiation of neuronal injury

The neurotrophins are a diverse family of peptides which activate specific tyrosine kinase-linked receptors. Over the past five decades, since the pioneering work of Levi-Montalcini and colleagues, the critical role that neurotrophins play in shaping the developing nervous system has become increasingly established. These molecules, which include the nerve growth factor (NGF)-related peptides, NGF, brain-derived neurotrophic factor (BDNF), NT-4/5 and NT-3, promote differentiation and survival in the developing nervous system, and to a lesser extent in the adult nervous system. As survival-promoting molecules, neurotrophins have been studied as potential neuroprotective agents, and have shown beneficial effects in many model systems. However, a surprising "dark side" to neurotrophin behavior has emerged from some of these studies implying that, under certain pathological conditions, neurotrophins may exacerbate, rather than alleviate, injury. How neurotrophins cause these deleterious consequences is a question which is only beginning to be answered, but initial work supports altered free radical handling or modification of glutamate receptor expression as possible mechanisms underlying these effects. This review will focus on evidence suggesting that neurotrophins may enhance injury under certain circumstances and on the mechanisms behind these injury-promoting aspects.