Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease

NEUROPHARMACOLOGY

卷:60

Article

Kovacs, Attila D.^1,2  Saje, Angelika⁴  Wong, Andrew⁴  Szenasi, Gabor⁵  Kiricsi, Peter⁵  Szabo, Eva⁵  Cooper, Jonathan D.⁴  Pearce, David A.^1,2,3,6 

[1] Univ Rochester, Sch Med & Dent, Ctr Neural Dev & Dis, Rochester, NY 14642 USA

[2] Univ Rochester, Sch Med & Dent, Dept Biochem & Biophys, Rochester, NY 14642 USA

[3] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA

[4] Kings Coll London, Pediat Storage Disorders Lab,Inst Psychiat, Dept Neurosci,James Black Ctr, Ctr Cellular Basis Behav,MRC Ctr Neurodegenerat, London SE5 9NU, England

[5] EGIS Pharmaceut Plc, Div Preclin Res, Budapest, Hungary

[6] Univ S Dakota, Sanford Sch Med, Dept Pediat, Sioux Falls, SD 57104 USA

关键词: Juvenile Batten disease;    Neuronal ceroid lipofuscinoses;    Cln3;    AMPA receptor;    EGIS-8332;    Rotarod;   

DOI  :  10.1016/j.neuropharm.2010.10.010

来源: Elsevier

【 摘 要 】

Mutations in the CLN3 gene cause juvenile Batten disease, a fatal pediatric neurodegenerative disorder. The Cln3-knockout (Cln3(Delta ex1-6)) mouse model of the disease displays many pathological characteristics of the human disorder including a deficit in motor coordination. We have previously found that attenuation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity in one-month-old Cln3(Delta ex1-6) mice resulted in an immediate improvement of their motor skills. Here we show that at a later stage of the disease, in 6-7-month-old Cln3(Delta ex1-6) mice, acute inhibition of AMPA receptors by a single intraperitoneal injection (1 mg/kg) of the non-competitive AMPA antagonist, EGIS-8332, does not have an immediate effect. Instead, it induces a delayed but prolonged improvement of motor skills. Four days after the injection of the AMPA antagonist, Cln3(Delta ex1-6) mice reached the same motor skill level as their wild type (WT) counterparts, an improvement that persisted for an additional four days. EGIS-8332 was rapidly eliminated from the brain as measured by HPLC-MS/MS. Histological analysis performed 8 days after the drug administration revealed that EGIS-8332 did not have any impact upon glial activation or the survival of vulnerable neuron populations in 7-month-old Cln3(Delta ex1-6) mice. We propose that temporary inhibition of AMPA receptors can induce a prolonged correction of the preexisting abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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