Abstract
Spinocerebellar ataxias are autosomal dominant diseases, associated in some types with a CAG repeat expansion, and characterised by a progressive loss of motor function. Currently, as there is no cure for most ataxias, treatment predominantly involves physical therapy. Various symptomatic drug treatments have been tried; however, published clinical studies have provided inconsistent results, likely due to small sample sizes, mixed patient populations and insensitive or subjective assessment scales. SCA1154Q transgenic mice display motor function impairments and ultimately a reduced number of cerebellar Purkinje neurons—characteristics comparable to most forms of sporadic and hereditary ataxias. We monitored motor function in SCA1154Q mice from 5 to 20 weeks of age and assessed the efficacy of four potential cerebellar modulatory drugs in attenuating deficits in rotor-rod performance. The drugs riluzole, amantadine, zolpidem and buspirone were selected based on their different mechanisms of action and their Food and Drug Administration (FDA)/Australian Therapeutic Goods Administration approval for other indications. SCA1154Q and C57/Bl6 wild-type mice were administered with four ascending acute doses of each drug, over 2 days. Following each dose, mice were assesed for motor function on the accelerating rotor-rod. None of the four drugs attenuated motor deficts in SCA1154Q mice at any dose; at FDA equivalent and higher dose administration of zolpidem and buspirone led to sedation in both strains. Our results suggest that the aforementioned drugs are likely to be ineffective for symptomatic treatment of SCA1 and most other ataxic patients and emphasise the need for comphrehensive drug studies prior to clinical use.
Similar content being viewed by others
References
Zoghbi HY, Orr HT. Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1. J Biol Chem. 2009;284:7425–9.
Zoghbi HY, Orr HT. Spinocerebellar ataxia type 1. Semin Cell Biol. 1995;6:29–35.
Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, Hashimoto K, et al. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron. 2002;34:905–19.
Cerminara NL. Cerebellar modules: individual or composite entities? J Neurosci. 2010;30:16065–7.
Schweighofer N, Doya K, Kuroda S. Cerebellar aminergic neuromodulation: towards a functional understanding. Brain Res Brain Res Rev. 2004;44:103–16.
Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74:839–45.
Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci. 2005;25:3312–22.
Gianutsos G, Chute S, Dunn JP. Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine. Eur J Pharmacol. 1985;110:357–61.
Botez MI, Botez-Marquard T, Elie R, Pedraza OL, Goyette K, Lalonde R. Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study. J Neurol Neurosurg Psychiatry. 1996;61:259–64.
Filla A, De Michele G, Orefice G, Santorelli F, Trombetta L, Banfi S, et al. A double-blind cross-over trial of amantadine hydrochloride in Friedreich's ataxia. Can J Neurol Sci. 1993;20:52–5.
Hassin-Baer S, Korczyn AD, Giladi N. An open trial of amantadine and buspirone for cerebellar ataxia: a disappointment. J Neural Transm. 2000;107:1187–9.
Kaefer V, Semedo JG, Kahl VFS, Von Borowsky RG, Gianesini J, Kist TBL, et al. DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine. J Appl Toxicol. 2010;30:745–53.
Clauss R, Sathekge M, Nel W. Transient improvement of spinocerebellar ataxia with zolpidem. N Engl J Med. 2004;351:511–2.
Murphy HM, Ihekoronze C, Wideman CH. Zolpidem-induced changes in activity, metabolism, and anxiety in rats. Pharmacol Biochem Behav. 2011;98:81–6.
Elliot EE, White JM. The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry. Neuropharmacology. 2001;40:717–21.
Fahey J, Grassi J, Reddi J, Greenblatt D. Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses. Pharmacol Biochem Behav. 2006;83:21–7.
Trouillas P, Xie J, Adeleine P, Michel D, Vighetto A, Honnorat J, et al. Buspirone, a 5-hydroxytryptamine1A agonist, is active in cerebellar ataxia. Results of a double-blind drug placebo study in patients with cerebellar cortical atrophy. Arch Neurol. 1997;54:749–52.
Assadi M, Campellone JV, Janson CG, Veloski JJ, Schwartzman RJ, Leone P. Treatment of spinocerebellar ataxia with buspirone. J Neurol Sci. 2007;260:143–6.
Lou JS, Goldfarb L, McShane L, Gatev P, Hallett M. Use of buspirone for treatment of cerebellar ataxia. An open-label study. Arch Neurol. 1995;52:982–8.
Holroyd-Leduc JM, Liu BA, Maki BE, Zecevic A, Hermann N, Black SE. The role of buspirone for the treatment of cerebellar ataxia in an older individual. Can J Clin Pharmacol. 2005;12:e218–21.
Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991;19:4293.
Swannick B. MIMS annual. 32nd ed. Sydney: UBM Medica Australia; 2008.
Center for Drug Evaluation and Research. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville, Maryland, USA: US Food and Drug Administration; 2005. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf
Carter RJ, Morton J, Dunnett SB. Motor coordination and balance in rodents. Curr Protoc Neurosci. 2001;8.12.1–8.12.14.
Fratkin JD, Vig PJ. Neuropathology of degenerative axtaxias. In: Subramony SH, Durr A, editors. Ataxic disorders: handbook of clinical neurology. Edinburgh: Elsevier; 2012. p. 111–26.
Ogawa M, Shigeto H, Yamamoto T, Oya Y, Wada K, Nishikawa T, et al. d-cycloserine for the treatment of ataxia in spinocerebellar degeneration. J Neurol Sci. 2003;210:53–6.
Saigoh K, Matsui K, Takahashi K, Nishikawa T, Wada K. The stereo-specific effect of d-serine ethylester and the d-cycloserine in ataxic mutant mice. Brain Res. 1998;808:42–7.
Cao Y-J, Dreixler JC, Couey JJ, Houamed KM. Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole. Eur J Pharmacol. 2002;449:47–54.
Poewe W, Mahlkne CP. Pharmacological treatment of Parkinson's disease. In: Watts RL, Standaert DG, Obeso JA, editors. Movement disorders. New York: McGraw Hill; 2011. p. 277–8.
Pogorelov VM, Lanthorn TH, Savelieva KV. Use of a platform in an automated open-field to enhance assessment of anxiety-like behaviors in mice. J Neurosci Methods. 2007;162:222–8.
Pokk P, Zharkovsky A. The effects of buspirone on the behaviour of control and stressed mice. J Physiol Pharmacol. 1998;49:175–85.
Acknowledgments
We gratefully acknowledge Monash University and the Bethlehem Griffiths Research Fund for financial assistance.
Conflict of interest
There are no potential conflicts of interest for any of the authors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nag, N., Tarlac, V. & Storey, E. Assessing the Efficacy of Specific Cerebellomodulatory Drugs for Use as Therapy for Spinocerebellar Ataxia Type 1. Cerebellum 12, 74–82 (2013). https://doi.org/10.1007/s12311-012-0399-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12311-012-0399-x