HYPERPLASTIC CHANGES WITHIN THE LEPTOMENINGES OF THE RAT AND MONKEY IN RESPONSE TO CHRONIC INTRACEREBROVENTRICULAR INFUSION OF NERVE GROWTH-FACTOR

Recombinant human nerve growth factor (rhNGF) was delivered for up to 6 months by continuous intrace-rebroventricular (icv) infusion to CD ( Sprague-Dawley derived) rats and cynomolgus monkeys. Rats (n = 15/sex/ group) received doses of 0 (vehicle), 6, 60, or 300 ng/day; monkeys (n = 5/sex/group) received 0, 0.6, 6, or 60 mu g/day of rhNGF. Animals t olerated icy infusion with no behavioral signs attributable to rhNGF. Body weight was transiently decreased in female rats at the highest do se. At the completion of dosing, histological examination in both spec ies revealed an increase in the thickness of the leptomeninges along t he ventral and lateral surfaces of the hindbrain and extending over th e dorsal aspect of the spinal cord, The change was present to varying degrees at all doses of rhNGF and tended to be more severe at higher d oses, At the light microscopic level, the leptomeninges contained laye rs of well-differentiated spindle-shaped cells and a plexus of axonal fibers, Cells were immunoreactive for S-100 protein and were associate d with art accumulation of Type IV collagen, suggesting Schwann cell o rigin, Electron microscopy revealed numerous fine caliber axons enshea thed by the presumptive Schwann cells, with myelination of individual axonal segments. These findings suggest that chronic icy delivery of r hNGF has stimulated axonal sprouting and secondary hyperplasia of Schw ann or Schwann-Like support cells within the pia-arachnoid. (C) 1997 A cademic Press.