In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3

Abstract

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder for which no curative therapy is available. The cause of this disease is the expansion of a CAG repeat in the so-called ATXN3 gene leading to an expanded polyglutamine stretch in the ataxin-3 protein. Although the function of ataxin-3 has been defined as a deubiquitinating enzyme, the pathogenic pathway underlying SCA3 remains to be deciphered. Besides others, also the glutamatergic system seems to be altered in SCA3. The antiglutamatergic substance riluzole has thus been suggested as a potential therapeutic agent for SCA3. To assess whether riluzole is effective in the treatment of SCA3 in vivo, we used a phenotypically well-characterized conditional mouse model previously generated by us. Treatment with 10 mg/kg riluzole in the drinking water was started when mice showed impairment in rotarod performance. Post-symptomatic treatment with riluzole carried out for a period of 10 months led to reduction of the soluble ataxin-3 level and an increase in ataxin-3 positive accumulations, but did not improve motor deficits measured by rotarod. There was also no positive effect on home cage behavior or body weight. We even observed a pronounced reduction of calbindin expression in Purkinje cells in riluzoletreated mice. Thus, long-term treatment with riluzole was not able to alleviate disease symptoms observed in transgenic SCA3 mice and should be considered with caution in the treatment of human patients.

Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3

“…Transgenic animals were identified by using DNA extracted from ear biopsy (Roche High Pure PCR Template Preparation Kit; Roche) as described in ref. 6 (Table S6).…”

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

“…Yet, a larger and longer study demonstrated no effect of riluzole in HD patients, suggesting that riluzole treatment may not useful in these patients. Postsymptomatic treatment of a conditional mouse model of MJD/SCA3 with riluzole led to no improvement of the motor uncoordination; intriguingly, riluzole chronic administration decreased the Calbindin expression in Purkinje cells of the cerebellum, suggesting possible toxicity . In contrast, a randomized clinical trial in SCA patients of different etiologies showed the short‐term efficacy (4 and 8 weeks) of riluzole in reducing disease symptoms.…”

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

“…Furthermore, the anti-glutamatergic compound riluzole was identified to improve ataxia symptoms in a randomized, double-blind, placebo-controlled pilot trial with 40 ataxia patients of different etiologies [ 188 ]. Given the proposed role of glutamatergic signaling for the induction of toxicity in SCA3 [ 49 ], riluzole was assessed in a SCA3 mouse model [ 128 ]. However, treatment with riluzole in the drinking water during 10 months did not provide an improvement in the rotarod performance, home cage activity, or body weight [ 128 ].…”

“…Given the proposed role of glutamatergic signaling for the induction of toxicity in SCA3 [ 49 ], riluzole was assessed in a SCA3 mouse model [ 128 ]. However, treatment with riluzole in the drinking water during 10 months did not provide an improvement in the rotarod performance, home cage activity, or body weight [ 128 ]. Surprisingly, riluzole-treated animals showed a higher number of damaged Purkinje neurons.…”