Neuroprotective effects of N-adamantyl-4-methylthiazol-2-amine against amyloid β-induced oxidative stress in mouse hippocampus.

We previously reported that N-adamantyl-4-methylthiazol-2-amine (KHG26693) suppresses amyloid beta (Aβ)-induced neuronal oxidative damage in cortical neurons. Here we investigated the mechanism and antioxidative function of KHG26693 in the hippocampus of Aβ-treated mice. KHG26693 significantly attenuated Aβ-induced TNF-α and IL-1β enhancements. KHG26693 decreased Aβ-mediated malondialdehyde formation, protein oxidation, and reactive oxygen species by decreasing the iNOS level. KHG26693 suppressed Aβ-induced oxidative stress through a mechanism involving glutathione peroxidase, catalase, and GSH attenuation. Aβ-induced MMP-2, cPLA2, and pcPLA2 expressions were almost completely attenuated by KHG26693 treatment, suggesting that Aβ-induced oxidative stress reduction by KHG26693 is, at least partly, caused by the downregulation of MMP-2 and cPLA2 activation. Compared with Aβ treatment, KHG26693 treatment upregulated Nrf2 and HO-1 expressions, suggesting that KHG26693 protects the brain from Aβ-induced oxidative damage, likely by maintaining redox balance through Nrf2/HO-1 pathway regulation. KHG26693 significantly attenuated Aβ-induced oxidative stress in the hippocampus of Aβ-treated mice.

Kim J ，Cho CH ，Hahn HG ，Choi SY ，Cho SW ... -  《-》

N-Adamantyl-4-methylthiazol-2-amine suppresses amyloid β-induced neuronal oxidative damage in cortical neurons.

Cho CH ，Kim EA ，Kim J ，Choi SY ，Yang SJ ，Cho SW ... -  《-》

Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats.

Thiazole derivatives are attractive candidates for drug development because they can be efficiently synthesized and are active against a number of diseases and conditions, including diabetes. In our present study, we investigated the anti-inflammatory and antioxidant properties of N-adamantyl-4-methylthiazol-2-amine (KHG26693), a new thiazole derivative, in a streptozotocin (STZ)-induced model of diabetes mellitus. STZ-induced diabetic rats were intraperitoneally administered KHG26693 (3mg/kg-body weight/day) for 4 weeks. KHG26693 administration significantly decreased blood glucose, triglycerides, and cholesterol and increased insulin. KHG26693 also suppressed several inflammatory responses in STZ-induced diabetic rats, as evidenced by decreased levels of serum tumor necrosis factor-α, interleukin-1β, and nitric oxide. Additionally, KHG26693 significantly modulated hepatic lipid peroxidation, catalase and superoxide dismutase activity, and the nonenzymatic antioxidant status (e.g., vitamins C and E), and reduced the glutathione content. These anti-inflammatory/antioxidative actions occurred as a result of the downregulation of inducible nitric oxide synthase and nuclear factor-kappa B. Taken together, our results suggest that KHG26693 successfully reduces the production of oxidative stress in STZ-induced diabetic rats by regulating the oxidation-reduction system, specifically increasing antioxidant capacity. Furthermore, KHG26693 treatment significantly reverted the key enzymes of glucose metabolism, such as glucokinase, glucose-6-phosphatase, glycogen synthase, glycogen phosphorylase, and fructose-1,6-bisphosphatase, to near-normal levels in liver tissues. These results indicate that KHG26693 normalizes disturbed glucose metabolism by enhancing glucose utilization and decreasing liver glucose production via insulin release, suggesting the possibility of future diabetes treatments.

Yang SJ ，Je Lee W ，Kim EA ，Dal Nam K ，Hahn HG ，Young Choi S ，Cho SW ... -  《-》

N-adamantyl-4-methylthiazol-2-amine suppresses lipopolysaccharide-induced brain inflammation by regulating NF-κB signaling in mice.

We report that N-adamantyl-4-methylthiazol-2-amine (KHG26693), a novel thiazole derivative, can prevent lipopolysaccharide (LPS)-induced brain inflammation in mice. In this LPS-induced model of brain inflammation, administration of KHG26693 effectively prevented increases in the levels of IL-1β, TNF-α, prostaglandin E2, malondialdehyde, and nitric oxide, and mitigated reductions in the levels of superoxide dismutase in the hippocampus. KHG26693 also prevented reductions in the levels of hippocampal brain-derived neurotrophic factors. Furthermore, pretreatment with KHG26693 prior to LPS treatment dramatically attenuated the elevation of inducible nitric oxide synthase and cyclooxygenase-2 protein levels. Moreover, pretreatment with KHG26693 significantly suppressed LPS-induced phosphorylation of NF-κB and IκBα through the inactivation of IKKβ. Additionally, KHG26693 caused the downregulation of LPS-induced cystathionine-b-synthase gene expression in the brain. Although the clinical relevance of our findings remains to be determined, our data suggest that KHG26693 might prevent neuronal cell injury via the reduction of inflammation and oxidative stress in the brain.

Cho CH ，Kim J ，Ahn JY ，Hahn HG ，Cho SW ... -  《-》

N-Adamantyl-4-methylthiazol-2-amine suppresses glutamate-induced autophagic cell death via PI3K/Akt/mTOR signaling pathways in cortical neurons.

Yang SJ ，Han AR ，Choi HR ，Hwang K ，Kim EA ，Choi SY ，Cho SW ... -  《-》