A SERINE-PROTEASE INHIBITOR, PRETENSE NEXIN-I, RESCUES MOTONEURONS FROM NATURALLY-OCCURRING AND AXOTOMY-INDUCED CELL-DEATH

Protease nexin I (PNI) is a member of the family of serine protease in hibitors (serpins) that have been shown to promote neurite outgrowth i rt vitro from different neuronal cell types. These include neuroblasto ma cells, hippocampal neurons, and sympathetic neurons. Free PNI prote in is markedly decreased in various anatomical brain regions, includin g hippocampus, of patients with Alzheimer disease. sere, we report tha t PNI rescued spinal motoneurons during the period of naturally occurr ing (programmed) cell death in the chicken in a dose-dependent fashion . Furthermore, PNI prevented axotomy-induced spinal motoneuron death i n the neonatal mouse. The survival effect of PNI on motoneurons during the period of programmed cell death was not associated with increased intramuscular nerve branching. PNI also significantly increased the n uclear size of motoneurons during the period of programmed cell death and prevented axotomy-induced atrophy of surviving motoneurons. These results are consistent with the possible role of PNI as a neurotrophic agent. They also support the idea that serine proteases or, more prec isely, the balance of proteases and serpins may be involved in regulat ing the fate of neuronal cells during development.