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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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.
KeywordsAlzheimer’s disease Beta-amyloid Thiazole derivative MAP kinase Nuclear factor kappa B Tau
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.
Conflict of interest
The authors have declared no conflict of interest.
- Adam-Vizia V, Starkov AA (2010) Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis 20(S2):S413–S426Google Scholar
- Cenini G, Sultana R, Memo M, Butterfield DA (2008) Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer’s disease. J Cell Mol Med 12(3):987–994PubMedCrossRefGoogle Scholar
- Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, Nordhoff E, Lurz R, Schugardt N, Rautenberg S, Herhaus C, Barnickel G, Bottcher H, Lehrach H, Wanker EE (2002) Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay. Proc Natl Acad Sci 99(S4):16400–16406PubMedCrossRefPubMedCentralGoogle Scholar
- Jho EH, Kang K, Oidovsambuu S, Lee EH, Jung SH, Shin IS, Nho CW (2013) Gymnaster koraiensis and its major components, 3,5-di-O-caffeoylquinic acid and gymnasterkoreayne B, reduce oxidative damage induced by tert-butyl hydroperoxide or acetaminophen in HepG2 cells. BMB Rep 46(10):513–518PubMedCrossRefGoogle Scholar
- Keown LE, Collins I, Cooper LC, Harrison T, Madin A, Mistry J, Reilly M, Shaimi M, Welch CJ, Clarke EE, Lewis HD, Wrigley JD, Best JD, Murray F, Shearman MS (2009) Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity. J Med Chem 52(11):3441–3444PubMedCrossRefGoogle Scholar
- Lee SY, Lee JW, Lee H, Yoo HS, Yun YP, Oh KW, Ha TY, Hong JT (2005) Inhibitory effect of green tea extract on beta-amyloid-induced PC12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. Brain Res Mol Brain Res 140(1–2):45–54PubMedCrossRefGoogle Scholar