Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease.
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.
Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.
Attila D
AD
Kovács
Angelika
A
Saje
Andrew
A
Wong
Serena
S
Ramji
Jonathan D
JD
Cooper
David A
DA
Pearce
D000375:Aging; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000627:therapeutic use*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009048:Motor Skills / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
C102229:CLN3 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine