Ketamine, a pediatric anesthetic, is widely used in clinical practice. There was growing evidence showing that ketamine can promote neuronal death in developing brains of both humans and animals. In this study, we used in vivo neonatal and juvenile mouse models to induce ketamine-related neurotoxicity in the hippocampus. Active caspase-3 and -9 proteins, which are responsible for the release of cytochrome C, and the mitochondrial translocation of p53, which is associated with mitochondrial apoptosis, were found to be significantly up-regulated in the ketamine-induced hippocampal neurotoxicity. Furthermore, we demonstrated that the levels of pyroptosis-related proteins, including caspase-1 and -11, NOD-like receptor family, pyrin domain containing 3 (NLRP3), and IL-1β and IL-18, significantly increased after multiple doses of ketamine administration. We speculated that ketamine triggered the formation of NLRP3 and caspase-1 complex and its translocation to the mitochondria. In consistent with this, ketamine treatment was found to induce pyroptosis in mouse primary hippocampal neurons, which was characterized by increased pore formation and elevated lactate dehydrogenase release in mitochondria. Silencing caspase-1 with lentivirus-mediated short hairpin RNA (shRNA) significantly decreased the levels of not only pyroptosis-related proteins but also mitochondrial apoptosis-associated proteins in mouse primary hippocampal neurons. We conclude that caspase-1-dependent pyroptosis is an important event which may be an essential pathway involved in the mitochondria-associated apoptosis in ketamine-induced hippocampal neurotoxicity.

Transforming growth factor-β (TGF-β) has been shown to induce apoptosis in normal hepatocytes and hepatoma cells both in vivo and in vitro. However, the mechanism by which TGF-β induces apoptosis is not clear. The antiapoptotic activity of antioxidants including N-acetyl-L-cysteine (Ac-Cys), ascorbic acid and a novel free radical scavenger, carboxyfullerene (C 60 ) on TGF-β-treated human hepatoma Hep3B cells was examined. Only the water-soluble hexacarboxylic acid derivative of C 60 was found to prevent TGF-β-induced apoptosis. Antiapoptotic activity of C 60 correlated its ability to eliminate TGF-β-generated reactive oxygen species (ROSs). However, C 60 did not interfere with TGF-β-activated PAI-1 promoter activity in the Hep3B cells. These results indicate that the signaling pathway of TGF-β-induced apoptosis may be related to the generation of ROSs and may be uncoupled from the TGF-β-activated gene promoter activity. Furthermore, the regioisomer of C 60 with a C 3 symmetry was more potent in protecting cells from apoptosis than that with a D 3 symmetry, and the C3 isomer had stronger interactions with lipid bilayers than the D 3 isomer. The spectroscopic analysis revealed that the C 3 isomer had stronger interactions with artificial lipid bilayers than the D 3 isomer. Therefore, our study indicates that C 60 may interact with membrane to eliminate TGF-β-induced ROSs and to prevent apoptosis occur in human hepatoma cells.Keywords : carboxyfullerene ; transforming growth factor-β ; apoptosis ; reactive oxygen species.Since its discovery, the pure carbon spheres of buckminster-inhibits cell proliferation, depending on the cell types and the presence of other growth factors [7Ϫ11]. Recent studies have fullerene (C 60 ) have generated great interest from many different branches of science and engineering. To investigate the chemical shown that TGF-β induces apoptosis in liver cells in vitro [12Ϫ 17], and transgenic mice overexpressing TGF-β develop continand physical characteristics of C 60 (and its larger fullerenes), many novel properties of C 60 were observed including its avid uing apoptotic death of hepatocytes as well as hepatic fibrosis in vivo [18]. Exogenous administration of TGF-β to rodents also reactivity with free radicals [1]. Buckminsterfullerenes, for example, are capable of adding multiple radicals to each molecule. results in a significant increase in hepatic cell death [13,15,19].These data strongly suggest that apoptosis induced by TGF-β The addition of as many as 34 methyl radicals to a single C 60 sphere has been reported, leading Krusic et al.[1] to characterize may be involved in various hepatic lesions. However, despite the identification of TGF-β receptors and the genes involved in C 60 as a 'radical sponge'. However, native C 60 is soluble only in organic solvents. Dugan et al. [2] have evaluated the possibility its downstream signaling pathway [20Ϫ27], the mechanism of TGF-β-induced apoptosis remains largely unknown. that the potent innate anti-oxidant properties of C 60 could be harn...

No abstract

No abstract

No abstract