title: Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson's Disease.
abstract: BACKGROUND
  Preclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson's disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration.
  
  
  OBJECTIVE
  To assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach.
  
  
  METHODS
  We used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection.
  
  
  RESULTS
  VCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration.
  
  
  CONCLUSIONS
  The results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Schneider
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, United States of America.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, United States of America.
authors.forename: Hyo-S
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Kidd
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D065842:Pars Compacta / Q000187:drug effects / Q000473:pathology; D014734:Vibrio cholerae / Q000201:enzymology
chemical_list: D018696:Neuroprotective Agents; D005677:G(M1) Ganglioside; D009439:Neuraminidase; D004298:Dopamine