DOSE-DEPENDENT DOXYCYCLINE-MEDIATED ADRENOCORTICOTROPIC HORMONE-SECRETION FROM ENCAPSULATED TET-ON PROOPIOMELANACORTIN NEURO2A CELLS IN THESUBARACHNOID SPACE

We previously reported that polymer-encapsulated mouse neuroblastoma c ells that are capable of secreting beta-endorphin may reduce pain sens itivity in rats after capsule implantation into the cerebrospinal flui d (CSF)filled subarachnoid space of the spinal cord. The neuroblastoma cells carry the proopiomelanocortin (POMC) gene that encodes the prec ursor of adrenocorticotropic hormone (ACTH) and beta-endorphin, To con trol the expression of these hormones in the present study, a promoter that is inducible by administration of tetracycline derivatives such as doxycycline (Dox) was linked to the POMC gene. Encapsulated cells i n the CSF space of rats stimulated by four intraperitoneal doses of Do x responded with ACTH expression as determined in a subsequence 36-hr in vitro incubation. The amount of ACTH released was dependent on the in vivo Dox dose. These findings indicate that gene expression in xeno geneic cells in the CSF space can be manipulated by injection of a rel atively innocuous drug, and suggest that this system may be applicable to cell transplantation therapy in patients with central nervous syst em diseases that require temporary control of ligand delivery.