Laquinimod treatment in the R6/2 mouse model

Gisa Ellrichmann,Oluwaseun Fatoba,Janine Brunner,Dominik Sehr,Michael Hayden,Konstanze F Winklhofer,Christiane Reick,Liat Hayardeny,Carsten Saft,Ralf Gold,Alina Blusch

doi:10.1038/s41598-017-04990-1

Abstract

The transgenic mouse model R6/2 exhibits Huntington’s disease (HD)-like deficits and basic pathophysiological similarities. We also used the pheochromocytoma-12 (PC12)-cell-line-model to investigate the effect of laquinimod on metabolic activity. Laquinimod is an orally administered immunomodulatory substance currently under development for the treatment of multiple sclerosis (MS) and HD. As an essential effect, increased levels of BDNF were observed. Therefore, we investigated the therapeutic efficacy of laquinimod in the R6/2 model, focusing on its neuroprotective capacity. Weight course and survival were not influenced by laquinimod. Neither were any metabolic effects seen in an inducible PC12-cell-line model of HD. As a positive effect, motor functions of R6/2 mice at the age of 12 weeks significantly improved. Preservation of morphologically intact neurons was found after treatment in the striatum, as revealed by NeuN, DARPP-32, and ubiquitin. Biochemical analysis showed a significant increase in the brain-derived neurotrophic factor (BDNF) level in striatal but not in cortical neurons. The number of mutant huntingtin (mhtt) and inducible nitric oxide synthase (iNOS) positive cells was reduced in both the striatum and motor cortex following treatment. These findings suggest that laquinimod could provide a mild effect on motor function and striatal histopathology, but not on survival. Besides influences on the immune system, influence on BDNF-dependent pathways in HD are discussed.

Highlights

The transgenic mouse model R6/2 exhibits Huntington’s disease (HD)-like deficits and basic pathophysiological similarities
We showed that laquinimod exerted beneficial effects on motor functions and some features of neurodegeneration in R6/2 HD transgenic mice
This is in line with earlier studies using the YAC128 mice, and another HD mouse model describing behavioral and motor improvement as well as reduced pathology in the striatum and certain cortical regions

Summary

Introduction

The transgenic mouse model R6/2 exhibits Huntington’s disease (HD)-like deficits and basic pathophysiological similarities. The number of mutant huntingtin (mhtt) and inducible nitric oxide synthase (iNOS) positive cells was reduced in both the striatum and motor cortex following treatment. These findings suggest that laquinimod could provide a mild effect on motor function and striatal histopathology, but not on survival. The expansion encodes a prolonged polyglutamine (polyQ) sequence that results in conformational change of the huntingtin (htt) protein and, induces the formation of intranuclear inclusions of mhtt in the brain These are pathogenic for HD and can be found in both patients and R6/2 mice (141–157 CAG repeats) as an experimental model of HD2. Promoting BDNF levels might be a potential therapeutic target in this devastating disease for which there is, to date, no known cure

Methods

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Conclusion