title: Treatment of the Ppt1(-/-) mouse model of infantile neuronal ceroid lipofuscinosis with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine.
abstract: The neuronal ceroid lipofuscinoses, a family of neurodegenerative lysosomal storage disorders, represent the most common cause of pediatric-onset neurodegeneration. The infantile form has a devastatingly early onset and one of the fastest-progressing disease courses. Despite decades of research, the molecular mechanisms driving neuronal loss in infantile neuronal ceroid lipofuscinosis remain unknown. We have previously shown that N-methyl-d-aspartate (NMDA)-type glutamate receptors in the Ppt1(-/-) mouse model of this disease exhibit a hyperfunctional phenotype and postulate that aberrant glutamatergic activity may contribute to neural pathology in both the mouse model and human patients. To test this hypothesis, we treated Ppt1(-/-) mice with the NMDA receptor antagonist memantine and assessed their response to the drug using an accelerating rotarod. At 20 mg/kg, memantine treatment induced a delayed but notable improvement in Ppt1(-/-) mice. Much remains to be assessed before moving to patient trials, but these results suggest memantine has potential as a treatment.
authors.affiliation: Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, SD, USA.
authors.forename: Rozzy
authors.initials: R
authors.lastname: Finn
authors.forename: Attila D
authors.initials: AD
authors.lastname: Kovács
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D045442:Rotarod Performance Test; D013869:Thiolester Hydrolases / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D008559:Memantine
keywords: Batten disease; NMDA receptor; infantile neuronal ceroid lipofuscinosis; memantine; rotarod