Document Detail

Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease.
MedLine Citation:
PMID:  22683643     Owner:  NLM     Status:  MEDLINE    
Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3(Δex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Δex1-6) mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3(Δex1-6) mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3(Δex1-6) mice. At a later stage of the disease, in 6-7-month-old Cln3(Δex1-6) mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3(Δex1-6) mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease.
Attila D Kovács; Angelika Saje; Andrew Wong; Serena Ramji; Jonathan D Cooper; David A Pearce
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-06
Journal Detail:
Title:  Neuropharmacology     Volume:  63     ISSN:  1873-7064     ISO Abbreviation:  Neuropharmacology     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-07-30     Completed Date:  2013-01-14     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  0236217     Medline TA:  Neuropharmacology     Country:  England    
Other Details:
Languages:  eng     Pagination:  769-75     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
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MeSH Terms
Cerebral Cortex / drug effects,  growth & development,  metabolism,  pathology
Disease Models, Animal*
Disease Progression*
Dose-Response Relationship, Drug
Drug Resistance*
Excitatory Amino Acid Antagonists / administration & dosage,  therapeutic use*
Memantine / administration & dosage,  therapeutic use*
Membrane Glycoproteins / genetics,  metabolism
Mice, 129 Strain
Mice, Knockout
Molecular Chaperones / genetics,  metabolism
Molecular Targeted Therapy
Motor Skills / drug effects
Nerve Tissue Proteins / antagonists & inhibitors,  genetics,  metabolism
Neuronal Ceroid-Lipofuscinoses / drug therapy*,  metabolism,  pathology
Neurons / drug effects,  metabolism,  pathology
Organ Specificity
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*,  metabolism
Grant Support
Reg. No./Substance:
0/CLN3 protein, mouse; 0/Excitatory Amino Acid Antagonists; 0/Membrane Glycoproteins; 0/Molecular Chaperones; 0/Nerve Tissue Proteins; 0/Receptors, N-Methyl-D-Aspartate; 19982-08-2/Memantine

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