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 resul ts in a variety of human neurodegenerative conditions, the possibility exists that intrathecal or intracerebroventricular delivery might pro vide more effective concentrations along the neuroaxis. In preparation to consider clinical trials, the potential neurotoxicologic effects o f chronic intrathecal GM1 were studied in ewes. Preliminary in vitro t ests first demonstrated the stability and compatibility of GM1 in impl anted pumps. Two groups of adult ewes were then implanted with either Therex or Infusaid continuous flow implantable pumps and chronic intra thecal catheters. Ewes were infused intrathecally with either preserva tive-free normal saline (n = 5) or GM1 (n = 7) 100 mug-10,000 mug/d fo r up to 24 wk. No abnormal behavioral responses were noted. Cerebrospi nal fluid analyzed for GM1 concentrations by thin layer chromatography revealed no evidence of GM1 accumulation. After the animals were kill ed, spinal cords were removed, fixed, sectioned, and stained. Histolog ic analysis revealed no generalized pattern of neuronal damage, demyel ination, gliosis, or axonopathy to distinguish intrathecal normal sali ne or GM1. In both treated and control groups, the only consistent fin ding was a pericatheter-associated compression of white matter with ax onal dilation, vacuolation, and occasional neuronal loss. Catheter tra cts in both groups were also associated with variable leptomeningeal f ibroproliferative changes in adjacent dura and pia, at times in conjun ction with more generalized duromeningeal thickening. In summary, chro nic intrathecal GM1 in doses up to 10 mg/d had no definable neuropatho logic consequences.