Change of intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF route.

Autor:	Jia C; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Lei Mon SS; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Yang Y; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Katsuyama M; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Yoshida-Tanaka K; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Nagata T; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Yoshioka K; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan., Yokota T; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.; NucleoTIDE and PepTIDE Drug Discovery Center, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2022 Dec 23; Vol. 31, pp. 182-196. Date of Electronic Publication: 2022 Dec 23 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2022.12.010
Abstrakt:	Antisense oligonucleotides (ASOs) are promising therapeutics for intractable central nervous system (CNS) diseases. For this clinical application, neurotoxicity is one of the critical limitations. Therefore, an evaluation of this neurotoxicity from a behavioral perspective is important to reveal symptomatic dysfunction of the CNS and elucidate the underlying molecular mechanism. We here exploited a behavioral analysis method to categorize and quantify the acute neurotoxicity of mice administered with toxic ASOs via intracerebroventricular injection. The toxic ASOs were found to reduce consciousness and locomotor function in mice in a dose-dependent manner. Mechanistically, we analyzed the effects of modulators against receptors or channels, which regulate calcium influx of neurons, on the ASO neurotoxicity. Modulators promoting calcium influx mitigated, whereas those hindering calcium influx increased, in vivo neurotoxicity of ASOs in mice. In an in vitro assay to evaluate intracellular free calcium levels using rat primary cortical neurons, toxic ASOs reduced the calcium levels. The findings of this study demonstrated the behavioral characteristics of ASO-induced neurotoxicity and revealed that changes in intracellular free calcium levels are a part of the mechanism underlying the neurotoxic effects of ASO. Competing Interests: T.Y. collaborates with Daiichi Sankyo Company, Ltd, Rena Therapeutics, Inc., Takeda Pharmaceutical Company, Ltd, and Toray Industries, Inc., and serves as the academic adviser for Rena Therapeutics, Inc., and Braizon Therapeutics, Inc. All other authors declare no competing interests. (© 2022.)
Databáze:	MEDLINE
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