The ultimate goal of this project is to improve clinical recovery following neuronal injury with the intervention of pharmacological doses of a neurotropic factor at the time of the insult. The ability of pharmacological doses of nerve growth factor (NGF) to ameliorate the deleterious effects of injury upon the neuronal cell body will be evaluated. NGF will be applied locally at the site of injury via a silicone chamber. From preliminary experiments, NGF applied in this fashion has been shown to protect against the normally-occurring cell death and to prevent the neuronal atrophy which occurs after axotomy. The following experiments will characterize this protection in injured sensory neurons. These experiments will provide insight into the pharmacological potential of NGF to ameliorate the effects of axotomy on sensory neurons (e.g. protect against cell death) and perhaps improve functional recovery after injury. In a more general sense, it will provide a model of ways in which other neurotropic factors yet to be discovered (e.g. for motor neurons) could likewise be used as pharmacological agents to enhance functional recovery following injury. Specifically, the studies will examine the neuronal cell body reaction in rat lumbar dorsal root ganglia (DRG) neurons after ipsilateral axotomy of the sciatic nerve. The influence of the type of lesion and surgical manipulation upon the DRG neuron will be evaluated systematically by counting DRG neurons and by performing computer-assisted morphometric analysis of neuronal size. The capability of NGF, supplied via reservoirs at the injury site, to alter the neuron reaction to the injury will be examined with similar techniques. The protective role of NGF will be studied in experiments evaluating regeneration following sciatic nerve injury to determine whether NGF will provide permanent effects and improvement in functional recovery. Regeneration will be evaluated with both physiological (pinch test and axonal transport of radioisotype) and histological (axonal counts and morphometric analysis) techniques. Changes in the neuropeptide levels (substance P and extralysosomal acid phosphatases) in the dorsal horn of the spinal cord will be measured after injury to compare the ability of NGF to alter transganglionic degenerative atrophy of the DRG neurons. Experiments will determine whether these changes are permanently altered after treatment with NGF. The final experiments will study axonal growth through an NGF-containing silicone chamber by using histologic and axonal transport techniques as in above experiments.
| Rich, K M; Luszczynski, J R; Osborne, P A et al. (1987) Nerve growth factor protects adult sensory neurons from cell death and atrophy caused by nerve injury. J Neurocytol 16:261-8 |
