| First Author | Kovács AD | Year | 2012 |
| Journal | Neuropharmacology | Volume | 63 |
| Issue | 5 | Pages | 769-75 |
| PubMed ID | 22683643 | Mgi Jnum | J:196533 |
| Mgi Id | MGI:5488695 | Doi | 10.1016/j.neuropharm.2012.05.040 |
| Citation | Kovacs AD, et al. (2012) Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease. Neuropharmacology 63(5):769-75 |
| abstractText | 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(Deltaex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Deltaex1-6) 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 alpha-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(Deltaex1-6) 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(Deltaex1-6) mice. At a later stage of the disease, in 6-7-month-old Cln3(Deltaex1-6) 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(Deltaex1-6) 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. |
