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2-Cyclopropylimino-3-methyl-1,3-thiazoline Hydrochloride Protects Against Beta-amyloid-induced Activation of the Apoptotic Cascade in Cultured Cortical Neurons

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Abstract

Aggregated β-amyloid, implicated in the pathogenesis of Alzheimer’s disease (AD), induces neurotoxicity by evoking a cascade of oxidative damage-dependent apoptosis in neurons. We investigated the molecular mechanisms underlying the protective effect of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377) against the beta-amyloid (Aβ25–35)-induced primary cortical neuronal cell neurotoxicity. Treatment with KHG26377 attenuated the Aβ25–35-induced apoptosis by decreasing the Bax/Bcl-2 ratio and suppressing the activation of caspase-3. A marked increase in calcium influx and in the level of reactive oxygen species together with a decrease in glutathione levels was found after Aβ25–35 exposure; however, KHG26377 treatment reversed these changes in a concentration-dependent manner. In addition, KHG26377 significantly suppressed Aβ25–35-induced toxicity concomitant with a reduction in the activation of extracellular signal-regulated kinases 1 and 2 and nuclear factor kappa B. The KHG26377-induced protection of neuronal cells against Aβ toxicity was also mediated by suppressing the expression of glycogen synthase kinase-3β, increasing the levels of β-catenin, and reducing the levels of phosphorylated tau. Our findings suggest that KHG26377 may modulate the neurotoxic effects of β-amyloid and provide a rationale for treatment of AD.

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Acknowledgments

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2041484), by the Korea Institute of Science and Technology Institutional Program, and by a Student Research Grant from the University of Ulsan College of Medicine, Seoul, Korea.

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The authors have declared no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 138-736, Korea

    Eun-A Kim, Chang Hun Cho & Sung-Woo Cho

  2. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791, Korea

    Hoh-Gyu Hahn

  3. Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 200-702, Korea

    Soo Young Choi

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  1. Eun-A Kim
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  2. Chang Hun Cho
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Correspondence to Sung-Woo Cho.

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Eun-A Kim and Chang Hun Cho have contributed equally to this study.

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Kim, EA., Cho, C.H., Hahn, HG. et al. 2-Cyclopropylimino-3-methyl-1,3-thiazoline Hydrochloride Protects Against Beta-amyloid-induced Activation of the Apoptotic Cascade in Cultured Cortical Neurons. Cell Mol Neurobiol 34, 963–972 (2014). https://doi.org/10.1007/s10571-014-0080-7

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