PREVENTION OF ACTIVITY-DEPENDENT NEURONAL DEATH - VASOACTIVE INTESTINAL POLYPEPTIDE STIMULATES ASTROCYTES TO SECRETE THE THROMBIN-INHIBITING NEUROTROPHIC SERPIN, PROTEASE NEXIN-I

Neuronal cell death occurs as a programmed, naturally occurring mechan ism and is the primary regressive event in central nervous system deve lopment, Death of neurons also occurs on an injury-induced basis after trauma and in human neurodegenerative diseases, Classical neurotrophi c factors can reverse this phenomenon in experimental models prompting initiation of clinical trials in conditions such as amyotrophic later al sclerosis and Alzheimer's disease, The glial-derived protease nexin I (PNI), a known promoter of neurite outgrowth in cell culture and a potent inhibitor of serine proteases, also enhances neuronal cell surv ival, PNI, in nanomolar concentrations, rescues spinal cord motor neur ons from both naturally-occurring programmed cell death in the chick e mbryo as well as following injury in the neonatal mouse. The potent ne uromodulator, vasoactive intestinal polypeptide (VIP), influences neur onal survival through glial-mediated factors and also induces secretio n of new ly synthesized astrocyte PNI. We now report that subnanomolar amounts of PNI enhance neuronal survival in mixed spinal cord cell cu lture, especially when neuronal cells were made electrically silent by administration of tetrodotoxin, The mediation of this effect is by in hibition of the multifunctional serine protease, thrombin, because hir udin, a thrombin-specific inhibitor, has the same effect, In addition, spinal cord neurons are exquisitely sensitive to thrombin because pic omolar and lower levels of the coagulation factor causes neuronal deat h, Thus, PNI is an astrocyte-derived, thrombin-inhibiting, activity-de pendent neurotrophic agent, enhanced secretion of which by VIP may be one approach to treat neurological disorders. (C) 1996 John Wiley & So ns, Inc.