Soluble TNF receptors partially protect injured motoneurons in the postnatal CNS

There is accumulating evidence that cytokines are involved in the functioni ng of the brain and the spinal cord. However, it has been controversial whe ther they exert a neurotoxic or a neuroprotective effect. To address this q uestion in vivo, we have examined the survival of injured motoneurons in a line of transgenic mice that overexpress the soluble form of tumour necrosi s factor receptor-1 (sTNFR1). In these animals, all of the circulating TNF and lymphotoxin-a are neutralized by the continuous expression of the solub le receptor. Following axotomy of the facial nerve in 7-day-old control mic e, we observed a loss of approximately 90% of the motoneurons at two weeks survival. In the transgenic mice under the same conditions, the percentage of motoneuron survival was increased two-fold (515 vs. 224) and varied as a function of the level of the circulating receptor. These results indicate that neutralization of endogenous TNF and lymphotoxin-alpha by means of ove rexpression of the soluble receptor can decrease cell death of injured moto neurons and suggest that these cytokines may play an important role in neur onal degeneration in the CNS following a lesion.