Neurotoxicology of chronic infusion of the ganglioside GM1 in the ewe: phase I. intrathecal administration.
Gangliosides, including GM1, provide a measure of improved functional recovery after ischemic, toxic, and traumatic brain injuries in animal studies. Since systemically injected GM1 has provided equivocal results in a variety of human neurodegenerative conditions, the possibility exists that intrathecal or intracerebroventricular delivery might provide more effective concentrations along the neuroaxis. In preparation to consider clinical trials, the potential neurotoxicologic effects of chronic intrathecal GM1 were studied in ewes. Preliminary in vitro tests first demonstrated the stability and compatibility of GM1 in implanted pumps. Two groups of adult ewes were then implanted with either Therex or Infusaid continuous flow implantable pumps and chronic intrathecal catheters. Ewes were infused intrathecally with either preservative-free normal saline (n = 5) or GM1 (n = 7) 100 micrograms-10,000 micrograms/d for up to 24 wk. No abnormal behavioral responses were noted. Cerebrospinal fluid analyzed for GM1 concentrations by thin layer chromatography revealed no evidence of GM1 accumulation. After the animals were killed, spinal cords were removed, fixed, sectioned, and stained. Histologic analysis revealed no generalized pattern of neuronal damage, demyelination, gliosis, or axonopathy to distinguish intrathecal normal saline or GM1. In both treated and control groups, the only consistent finding was a pericatheter-associated compression of white matter with axonal dilation, vacuolation, and occasional neuronal loss. Catheter tracts in both groups were also associated with variable leptomeningeal fibroproliferative changes in adjacent dura and pia, at times in conjunction with more generalized duromeningeal thickening. In summary, chronic intrathecal GM1 in doses up to 10 mg/d had no definable neuropathologic consequences.
Coombs
D W
DW
Institute for Spinal Drugs and Neurotoxicology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756.
Colburn
R W
RW
McCarthy
L E
LE
DeLeo
J A
JA
Hoopes
P J
PJ
Twitchell
B B
BB
D000818:Animals; D002240:Carbohydrate Sequence; D004353:Drug Evaluation, Preclinical; D005260:Female; D005677:G(M1) Ganglioside / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000633:toxicity*; D007260:Infusion Pumps; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008969:Molecular Sequence Data; D012756:Sheep; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling
D005677:G(M1) Ganglioside