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 mechanism and is the primary regressive event in central nervous system development. Death of neurons also occurs on an injury-induced basis after trauma and in human neurodegenerative diseases. Classical neurotrophic factors can reverse this phenomenon in experimental models prompting initiation of clinical trials in conditions such as amyotrophic lateral 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 survival. PNI, in nanomolar concentrations, rescues spinal cord motor neurons from both naturally-occurring programmed cell death in the chick embryo as well as following injury in the neonatal mouse. The potent neuromodulator, vasoactive intestinal polypeptide (VIP), influences neuronal survival through glial-mediated factors and also induces secretion of newly synthesized astrocyte PNI. We now report that subnanomolar amounts of PNI enhance neuronal survival in mixed spinal cord cell culture, especially when neuronal cells were made electrically silent by administration of tetrodotoxin. The mediation of this effect is by inhibition of the multifunctional serine protease, thrombin, because hirudin, a thrombin-specific inhibitor, has the same effect. In addition, spinal cord neurons are exquisitely sensitive to thrombin because picomolar and lower levels of the coagulation factor causes neuronal death. Thus, PNI is an astrocyte-derived, thrombin-inhibiting, activity-dependent neurotrophic agent, enhanced secretion of which by VIP may be one approach to treat neurological disorders.
Festoff
B W
BW
Neurobiology Research Laboratory, Veterans Affairs Medical Center, Kansas City, Missouri 64128, USA. serpin@kuhub.cc.ukans.edu
Nelson
P G
PG
Brenneman
D E
DE
D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D058255:Protease Nexins; D051381:Rats; D011956:Receptors, Cell Surface; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013268:Stimulation, Chemical; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D015842:Serine Proteinase Inhibitors; D014660:Vasoactive Intestinal Peptide; D013004:Somatostatin; D013917:Thrombin