When a single generalized seizure was elicited 10 min following
phenytoin administration, average phenytoin brain dialysate levels were significantly lower (up to 45%) than those of control animals. During a self-sustained status epilepticus, phenytoin access to the site of seizure initiation tended to be lower in the early phase following drug administration, but reached control level 2 h later.
The data clearly demonstrate that seizure-induced alterations in BBB integrity and function do not increase extracellular brain levels of phenytoin in affected brain regions, but rather tend to decrease the eFT-508 ic50 free concentration of phenytoin in the extracellular compartment. (C) 2011 Elsevier Ltd. All rights reserved.”
“Nuclear factor E2 related Evofosfamide purchase factor-2 (Nrf2) transcription factor is one of the main regulators of intracellular redox balance and a sensor of oxidative and electrophilic stress. Low Nrf2 activity is usually associated with carcinogenesis, but Nrf2 is also considered as an oncogene because it increases survival of transformed cells. Because intracellular redox balance alterations :ire involved in both senescence and tumorigenesis, we investigated the impact of Nrf2 genetic deletion on cellular immortalization and life span of murine embryonic Fibroblasts. We report that Nrf2 genetic deletion promotes immortalization due to
an early loss of p53-dependent gene expression. However, compared with control cells, immortalized Nrf2-/- murine embryonic fibroblasts exhibited decreased growth, lower cycl in E levels, and impaired expression of NQO1 and cytochrome b(5) reductase. Moreover, SirT1 was also significantly reduced in immortalized Nrf2-/- murine embryonic fibroblasts, and these cells exhibited shorter life
span. Our results underscore the dual role of Nrf2 in protection against carcinogenesis and in the delay of cellular aging.”
“Two-pore-domain K(+) (K(2)P) channels are highly expressed in neurons and cardiac myocytes. In this JIB04 concentration study we investigated the potency of the antidepressant fluoxetine to inhibit brain and cardiac K(2)P channels, TREK-1, TASK-1 and THIK-1. Maximal sensitivity was detected for TREK-1, which was inhibited by 77% when expressed in HEK-293 cells and Xenopus oocytes. Alternative translation initiation (ATI) generates two different protein products from a single transcript of TREK-1. Electrophysiological analysis of two polypeptides engineered by mutagenesis (TREK-1[M53I], TREK-1[Delta N52]) revealed reduced current amplitude and K(+) selectivity of the truncated TREK-1 isoform. The sensitivity of TREK-1[Delta N52] to fluoxetine decreased by 70%, indicating that the first 52 amino acids are essential for TREK-1 sensitivity to this drug. (C) 2011 Elsevier Ltd. All rights reserved.”
“Werner syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase.