PP  Vol.10 No.4 , April 2019
The Effects of Rufinamide on in Vitro Spinal Muscular Atrophy Model
ABSTRACT
Spinal muscular atrophy (SMA) is devastating genetic disease characterized by progressive loss of motor neuron and skeletal muscle weakness. SMA is the most common lethal genetic disease in infancy. SMA is caused by deletion or mutation of SMN1 gene and subsequent lack of SMN protein. Our purpose in this study was to evaluate the therapeutic potential of rufinamide, an antiepileptic drug. In this study, SMA patient-derived fibroblasts and differentiated spinal motor neurons (MNs) using SMA patient-derived iPSCs were used as in vitro SMA model. SMN mRNA was significantly increased by addition of rufinamide in type III SMA patient-derived fibroblasts. Furthermore, rufinamide stimulated neurite elongation in type III SMA patient derived-iPSCs-MNs. In contrast of the result using type III SMA patient-derived fibroblasts, the expression level of SMN mRNA was not changed after rufinamide treatment in type I SMA patient-derived fibroblasts, and rufinamide did not affect neurite outgrowth in type I SMA patients derived-iPSCs-MNs. These findings indicate that rufinamide may be one of the potential candidate drugs for mild type of SMA.
Cite this paper
Ando, S. , Sato, A. , Funato, M. , Ohuchi, K. , Inagaki, S. , Nakamura, S. , Shimazawa, M. , Kaneko, H. and Hideaki Hara, H. (2019) The Effects of Rufinamide on in Vitro Spinal Muscular Atrophy Model. Pharmacology & Pharmacy, 10, 159-168. doi: 10.4236/pp.2019.104014.
References
[1]   Crawford, T.O. and Pardo, C.A. (1996) The Neurobiology of Childhood Spinal Muscular Atrophy. Neurobiology of Disease, 3, 97-110.
https://doi.org/10.1006/nbdi.1996.0010

[2]   Lefebvre, S., Bürglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., et al. (1995) Identification and Characterization of a Spinal Muscular Atrophy-Determining Gene. Cell, 80, 155-165.
https://doi.org/10.1016/0092-8674(95)90460-3

[3]   Lorson, C.L., Hahnen, E., Androphy, E.J. and Wirth, B. (1999) A Single Nucleotide in the SMN Gene Regulates Splicing and is Responsible for Spinal Muscular Atrophy. Proceedings of the National Academy of Sciences of the United States of America, 96, 6307-6311.

[4]   Prior, T.W., Snyder, P.J., Rink, B.D., Pearl, D.K., Pyatt, R.E., Mihal, D.C., Conlan, T., Schmalz, B., Montgomery, L., Ziegler, K., Noonan, C., Hashimoto, S. and Garner, S. (2010) Newborn and Carrier Screening for Spinal Muscular Atrophy. American Journal of Medical Genetics Part A, 152A, 1608-1616.
https://doi.org/10.1002/ajmg.a.33474

[5]   Zerres, K., Wirth, B. and Rudnik-Schoneborn, S. (1997) Spinal Muscular Atrophy—Clinical and Genetic Correlations. Neuromuscular Disorders, 7, 202-207.

[6]   Finkel, R.S., Chiriboga, C.A., Vajsar, J., Day, J.W., Montes, J., De Vivo, D.C., et al. (2016) Treatment of Infantile-Onset Spinal Muscular Atrophy with Nusinersen: A Phase 2, Open-Label, Dose-Escalation Study. The Lancet, 388, 3017-3026.
https://doi.org/10.1016/S0140-6736(16)31408-8

[7]   Gresham, J., Eiland, L.S. and Chung, A.M. (2010) Treating Lennox-Gastaut Syndrome in Epileptic Pediatric Patients with Third Generation Rufinamide. Neuropsychiatric Disease and Treatment, 6, 639-645.

[8]   Park, J.A. and Lee, C.H. (2018) Effect of Rufinamide on the Kainic Acid-Induced Excitotoxic Neuronal Death in the Mouse Hippocampus. Archives of Pharmacal Research, 41, 776-783.
https://doi.org/10.1007/s12272-018-1043-1

[9]   Swoboda, K.J., Scott, C.B., Reyna, S.P., Prior, T.W., LaSalle, B., Sorenson, S.L., et al. (2009) Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy. PLoS ONE, 4, e5268.
https://doi.org/10.1371/journal.pone.0005268

[10]   Darbar, I.A., Plaggert, P.G., Resende, M.B., Zanoteli, E. and Reed, U.C. (2011) Evaluation of Muscle Strength and Motor Abilities in Children with Type II and III Spinal Muscle Atrophy Treated with Valproic Acid. BMC Neurology, 21, 686.

[11]   Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F.A., Raschke, H., Blumcke, I., et al. (2003) Valproic Acid Increases the SMN2 Protein Level: A Well-Known Drug as a Potential Therapy for Spinal Muscular Atrophy. Human Molecular Genetics, 12, 2481-2489.
https://doi.org/10.1093/hmg/ddg256

[12]   Merlini, L., Solari, A., Vita, G., Bertini, E., Minetti, C., Mongini, T., Mazzoni, E., Angelini, C. and Morandi, L. (2003) Role of Gabapentin in Spinal Muscular Atrophy: Results of a Multicenter, Randomized Italian Study. Journal of Child Neurology, 18, 537-541.
https://doi.org/10.1177/08830738030180080501

[13]   Ohuchi, K., Funato, M., Kato, Z., Seki, J., Kawase, C., Tamai, Y., Ono, Y., Nagahara, Y., Noda, Y., Kameyama, T., Ando, S., Tsuruma, K., Shimazawa, M., Hara, H. and Kaneko H. (2016) Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog. STEM CELLS Translational Medicine, 5, 152-163.
https://doi.org/10.5966/sctm.2015-0059

[14]   Hua, Y., Vickers, T.A., Okunola, H.L., Bennett, C.F. and Krainer, A.R. (2008) Antisense Masking of an hnRNP A1/A2 Intronic Splicing Silencer Corrects SMN2 Splicing in Transgenic Mice. American Journal of Human Genetics, 82, 834-848.
https://doi.org/10.1016/j.ajhg.2008.01.014

[15]   Hua, Y., Sahashi, K., Rigo, F., Hung, G., Horev, G., Bennett, C.F. and Krainer, A.R. (2011) Peripheral SMN Restoration is Essential for Long-Term Rescue of a Severe Spinal Muscular Atrophy Mouse Model. Nature, 478, 123-126.
https://doi.org/10.1038/nature10485

[16]   Sumner, C.J., Huynh, T.N., Markowitz, J.A., Perhac, J.S., Hill, B., Coovert, D.D. Schussler, K., Chen, X., Jarecki, J., Burghes, A.H., Taylor, J.P. and Fischbeck, K.H. (2003) Valproic Acid Increases SMN Levels in Spinal Muscular Atrophy Patient Cells. Annals of Neurology, 54, 647-654.
https://doi.org/10.1002/ana.10743

[17]   Chen, Y.C., Chang, J.G., Jong, Y.J., Liu, T.Y. and You, C.Y. (2015) High Expression Level of Tra2-β1 Is Responsible for Increased SMN2 Exon 7 Inclusion in the Testis of SMA Mice. PLoS ONE, 10, e0120721.
https://doi.org/10.1371/journal.pone.0120721

[18]   Ohtsuka, Y., Yoshinaga, H., Shirasaka, Y., Takayama, R., Takano, H. and Iyoda, K. (2014) Rufinamide as an Adjunctive Therapy for Lennox-Gastaut Syndrome: A Randomized Double-Blind Placebo-Controlled Trial in Japan. Epilepsy research, 108, 1627-1636.
https://doi.org/10.1016/j.eplepsyres.2014.08.019

[19]   Gáll, Z., Vancea, S., Szilágyi, T., Gáll, O. and Kolcsár, M. (2015) Dose-Dependent Pharmacokinetics and Brain Penetration of Rufinamide Following Intravenous and Oral Administration to Rats. European Journal of Pharmaceutical Sciences, 68, 106-113.
https://doi.org/10.1016/j.ejps.2014.12.012

[20]   Rathod, R., Havlicek, S., Frank, N., Blum, R. and Sendtner, M. (2012) Laminin Induced Local Axonal Translation of β-Actin mRNA Is Impaired in SMN-Deficient Motoneurons. Histochemistry and Cell Biology, 138, 737-748.
https://doi.org/10.1007/s00418-012-0989-1

[21]   Liu, H., Lu, J., Chen, H., Du, Z., Li, X.J. and Zhang, S.C. (2015) Spinal Muscular Atrophy Patient-Derived Motor Neurons Exhibit Hyperexcitability. Scientific Reports, 5, Article No. 12189.
https://doi.org/10.1038/srep12189

 
 
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