SUMMERYKetamine (KTM), a N-methyl-D-aspartate (NMDA) receptor antagonist, was found to has an anti-inflammatory effect, but some patients suffered from exacerbated pro-inflammatory reactions after anesthesia with KTM. The present study was aimed to examine the underlying mechanism of pro-inflammatory effects of KTM. In this study, RAW264.7 cells were exposed to KTM and NMDA alone or combined for 30 min before lipopolysaccharide (LPS) stimulation. The expression levels of IL-6 and TNF-α were detected by RT-PCR and ELISA, and those of NMDA receptors by RT-PCR in RAW264.7 cells. Additionally, the TLR4 expression was determined by RT-PCR and flow cytometry, respectively. The results showed that in RAW264.7 cells, KTM alone promoted the TLR4 expression, but did not increase the expression of IL-6 or TNF-α. In the presence of LPS, KTM caused a significantly higher expression of IL-6 and TNF-α than LPS alone. NMDA could neither alter the IL-6 and TNF-α mRNA expression, nor reverse the enhanced expression of IL-6 and TNF-α mRNA by KTM in LPS-challenged cells. After TLR4-siRNA transfection, RAW264.7 cells pretreated with KTM no longer promoted the IL-6 and TNF-α expression in the presence of LPS. In conclusion, KTM accelerated LPS-induced inflammation in RAW264.7 cells by promoting TLR4 expression, independent of NMDA receptor.

2011-08-01·Drug Metabolism and Disposition2区 · 医学

Effects of Ketamine on Human UDP-Glucuronosyltransferases In Vitro Predict Potential Drug-Drug Interactions Arising from Ketamine Inhibition of Codeine and Morphine Glucuronidation

2区 · 医学

Article

作者: Raungrut, Pritsana ; Evans, Allan M. ; Chau, Nuy ; Miners, John O. ; Uchaipichat, Verawan ; Janchawee, Benjamas

In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC(50) values were <100 μM only for UGT2B4, UGT2B7, and UGT2B15. UGT2B7 catalyzes MOR 3- and 6-glucuronidation and the 6-glucuronidation of COD, with an additional substantial contribution of UGT2B4 to the latter reaction. Consistent with the effects of KTM on the activities of recombinant UGT2B enzyme activities, KTM competitively inhibited human liver microsomal MOR and COD glucuronidation. K(i) values for KTM inhibition of MOR 3- and 6-glucuronidation and COD 6-glucuronidation by human liver microsomes supplemented with 2% bovine serum albumin were 5.8 ± 0.1, 4.6 ± 0.2, and 3.5 ± 0.1 μM, respectively. Based on the derived inhibitor constants, in vitro-in vivo extrapolation was used to predict the effects of anesthetic and analgesic doses of KTM on MOR and COD clearances. Potentially clinically significant interactions (>50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation.

Experimental and Therapeutic Medicine

CB1 receptor mediates anesthetic drug ketamine‑induced neuroprotection against glutamate in HT22 cells

Article

作者: Bao, He ; Wang, Chen ; Xue, Xiaorong ; Guo, Qi ; Hu, Bin

The anesthetic drug, ketamine (KTM) has been shown to induce therapeutic effects against major depressive disorder (MDD), however the related underlying mechanisms remain unclear. In the present study, HT22 neuronal cells were treated with glutamate to imitate oxidative stress injury in MDD, and it was hypothesized that the cannabinoid type 1 (CB1) receptor mediates KTM-induced neuroprotection via ameliorating mitochondrial function in glutamate-treated neuronal cells. Compared with the control, glutamate decreased cell viability and intracellular antioxidants, including glutathione (GSH), catalase and superoxide dismutase 2 levels, and inhibited mitochondrial function simultaneously. Moreover, glutamate increased lactate dehydrogenase release, cellular apoptosis level, cleaved caspase-3 expression and intracellular oxidants, such as reactive oxygen species, oxidized GSH and mitochondrial superoxide in the cells. The presence of KTM, however, significantly decreased the glutamate-induced oxidative stress injury, ameliorated the antioxidant/oxidant levels in the cells, enhanced mitochondrial function and upregulated CB1 receptor expression (P<0.05). Co-administration of the CB1 receptor antagonist AM251 markedly abolished the KTM-induced cytoprotective effects and ameliorations of antioxidant/oxidant levels and mitochondrial function, and also reversed CB1 upregulation (P<0.05). These observations indicated that KTM decreases the oxidative stress injury caused by glutamate in HT22 neuronal cells, and the neuroprotective effects may be mediated by the CB1 receptor.

100 项与安纳白介素生物类似药 (Paras Biopharmaceuticals) 相关的药物交易

登录后查看更多信息