Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1Reportar como inadecuado




Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Molecular Brain

, 6:48

First Online: 19 November 2013Received: 09 August 2013Accepted: 28 October 2013

Abstract

BackgroundSpinocerebellar ataxia type 1 SCA1 is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice Q154-Q2 as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.

ResultsSymptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator PAM, Ro0711401 10 mg-kg, s.c., caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 10 mg-kg, s.c., caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 2.5 mg-kg, i.p., further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.

ConclusionsThese data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel -cerebellum-specific-, effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

KeywordsmGlu1 receptor Ro0711401 mGlu5 receptor VU0360172 JNJ16259685 Spinocerebellar ataxia type 1 Purkinje cell Motor coordination AbbreviationsmGluMetabotropic glutamate

SCA1Spinocerebellar ataxia type-1

PAMPositive allosteric modulator

NAMNegative allosteric modulator

ATXN1Ataxin-1

InsP3Inositol-1,4,5-trisphosphate

DAGDiacylglicerol

PKCProtein kinase C

AMPA2-amino-3-3-hydroxy-5-methyl-isoxazol-4-ylpropanoic acid

LTDLong term depression.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-6606-6-48 contains supplementary material, which is available to authorized users.

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Autor: Serena Notartomaso - Cristina Zappulla - Francesca Biagioni - Milena Cannella - Domenico Bucci - Giada Mascio - Pamela Scar

Fuente: https://link.springer.com/







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