title: 2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride protects against beta-amyloid-induced activation of the apoptotic cascade in cultured cortical neurons.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 138-736, Korea.
authors.forename: Eun-A
authors.initials: EA
authors.lastname: Kim
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Cho
authors.forename: Hoh-Gyu
authors.initials: HG
authors.lastname: Hahn
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Cho
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C550808:2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013844:Thiazoles; D051996:Transcription Factor RelA; C074636:amyloid beta-protein (25-35); D051176:beta Catenin; D016875:tau Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D005978:Glutathione; D002118:Calcium