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The Effects of Rufinamide on <i>in Vitro</i>Spinal Muscular Atrophy Model

Pharmacology & Pharmacy 2019年第4期10卷 159-168页

作者： Shiori Ando Arisu Sato michinori funato Kazuki Ohuchi Satoshi Inagaki Shinsuke Nakamura Masamitsu Shimazawa Hideo Kaneko Hideaki Hideaki Hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Clinical Research National Hospital Organization Nagara Medical Center Gifu Japan

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.

关键词： Spinal Muscular Atrophy Rufinamide iPSCs

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Identification of the Stress Which Causes Optineurin Aggregation

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Neuroscience & Medicine 2019年第2期10卷 150-161页

作者： Satoshi Inagaki michinori funato Junko Seki Chizuru Kawase Kazuki Ohuchi Shiori Ando Shinsuke Nakamura Masamitsu Shimazawa Hideo Kaneko Hideaki Hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Clinical Research National Hospital Organization Nagara Medical Center Gifu Japan

Glaucoma is a common neurodegenerative disease that can cause blindness and occurs worldwide. Currently, lowering intraocular pressure is the only therapy available to protect retinal ganglion cells (RGCs). However, this therapy does not prevent RGC death in all patients. Therefore, new therapeutic approaches for glaucoma are urgently required, and neuroprotection of RGCs is a focus for many researchers. Optineurin (OPTN) is one of the normal tension glaucoma (NTG) relative genes, while mutant OPTN can form a characteristic aggregation, causing RGC death. Hence, elucidation of the mechanism of OPTN aggregation might provide a clue to help understand RGC death. To examine whether non-mutant OPTN could also aggregate, we pharmacologically induced some glaucoma-related stresses, such as endoplasmic reticulum (ER) stress, glutamate toxicity, activation of TNF-α signaling, mitochondrial dysfunction, and autophagic flux impairment. Our results showed that ER stress, TNF-α signaling, and autophagic flux are involved in OPTN aggregation. Furthermore, our data indicated that increased ER stress, activation of TNF-α signaling, and impaired autophagic flux induce OPTN aggregation, suggesting that OPTN aggregation might be an important therapeutic target not only for familial NTG with mutated OPTN but also for patients with glaucoma more generally.

关键词： Glaucoma Induced Pluripotent Stem Cells Retinal Ganglion Cells Optineurin Protein Aggregation

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