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 intracerebroventricular (i.c.v.) 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 microg/day of rhNGF. Animals tolerated i.c.v. infusion with no behavioral signs attributable to rhNGF. Body weight was transiently decreased in female rats at the highest dose. At the completion of dosing, histological examination in both species revealed an increase in the thickness of the leptomeninges along the ventral and lateral surfaces of the hindbrain and extending over the 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 doses. At the light microscopic level, the leptomeninges contained layers of well-differentiated, spindle-shaped cells and a plexus of axonal fibers. Cells were immunoreactive for S-100 protein and were associated with an accumulation of Type IV collagen, suggesting Schwann cell origin. Electron microscopy revealed numerous fine caliber axons ensheathed by the presumptive Schwann cells, with myelination of individual axonal segments. These findings suggest that chronic i.c.v. delivery of rhNGF has stimulated axonal sprouting and secondary hyperplasia of Schwann or Schwann-like support cells within the pia-arachnoid.
Day-Lollini
P A
PA
Bioservices, Center for Biological Research, and Roche Bioscience, Palo Alto, California 94304-1397, USA.
Stewart
G R
GR
Taylor
M J
MJ
Johnson
R M
RM
Chellman
G J
GJ
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002404:Catheterization; D002455:Cell Division / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008252:Macaca fascicularis; D008297:Male; D008578:Meninges / Q000473:pathology*; D008854:Microscopy, Electron; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013045:Species Specificity; D013194:Staining and Labeling; D013997:Time Factors
D009414:Nerve Growth Factors; D011994:Recombinant Proteins