Studies in rodent brain slices suggest that seizures in focal epilepsies are sustained and propagated by the reciprocal interaction between neurons and astroglial cells

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Experience-dependent plasticity in the developing visual cortex depends on electrical activity and molecular signals involved in stabilization or removal of inputs. Extracellular signal-regulated kinase 1,2 (also called p42/44 mitogen-activated protein kinase) activation in the cortex is regulated by both factors. We show that two different inhibitors of the ERK pathway suppress the induction of two forms of long-term potentiation (LTP) in rat cortical slices and that their intracortical administration to monocularly deprived rats prevents the shift in ocular dominance towards the nondeprived eye. These results demonstrate that the ERK pathway is necessary for experience-dependent plasticity and for LTP of synaptic transmission in the developing visual cortex.

Objective-The interaction of advanced glycation end products (AGEs) with their main receptor RAGE in endothelial cells induces intracellular generation of reactive oxygen species (ROS) and the expression of vascular cell adhesion molecule (VCAM)-1. We investigated the role of distinct sources of ROS, including the mitochondrial electron transport chain, NAD(P)H oxidase, xanthine oxidase, and arachidonic acid metabolism, in AGE-induced VCAM-1 expression. Methods and Results-The induction of ROS and VCAM-1 by AGEs in cultured human umbilical vein endothelial cells was specifically blocked by an anti-RAGE antibody. The inhibition of NAD(P)H oxidase by apocynin and diphenylene iodonium, and of the mitochondrial electron transport system at complex II by thenoyltrifluoroacetone (TTFA), significantly inhibited both AGE-induced ROS production and VCAM-1 expression, whereas these effects were potentiated by rotenone and antimycin A, specific inhibitors of mitochondrial complex I and III, respectively. The inhibition of Cu/Zn superoxide dismutase inhibited both ROS and VCAM-1 induction, indicating that H 2 O 2 by this source is involved as a mediator of VCAM-1 expression by AGEs. Conclusions-Altogether, these results demonstrate that ROS generated by both NAD(P)H-oxidase and the mitochondrial electron transport system are involved in AGE signaling through RAGE, and indicate potential targets for the inhibition of the atherogenic signals triggered by AGE-RAGE interaction. Key Words: diabetes mellitus Ⅲ endothelium Ⅲ reactive oxygen species Ⅲ signal transduction Ⅲ superoxide Ⅲ vascular biology Ⅲ VCAM-1 Ⅲ adhesion molecules T he formation and accumulation of advanced glycation end products (AGEs) induce vascular cellular activation and inflammation mainly through interaction of AGEs with specific receptors. The main pathological consequence of AGE interaction with the main endothelial surface receptor for AGEs (RAGE) is the induction of intracellular reactive oxygen species (ROS). 1 ROS would in turn activate the redox-sensitive transcription nuclear factor NF-B, a pleiotropic regulator of many "response-to-injury" genes, such as vascular cell adhesion molecule-1 (VCAM-1). 2,3 Several reports have linked ROS with p21ras, MAP kinases, cdc42/rac, and extracellular signal regulated kinase (ERK)-1 and -2 in the signal transduction from RAGE to NF-B-induced inflammatory molecules. 1,4 -8 Each of these pathways is closely linked to AGE binding to RAGE, because blockade of the receptor with either anti-RAGE IgG or excess soluble (s)RAGE prevents their activation. 9 The tethering of AGEs to the cell surface by RAGE is not enough to generate ROS and cellular activation, because the RAGE carboxy-terminal cytosolic tail, containing known signaling phosphorylation sites, kinase domains, and other activation sites, is critical for RAGE-dependent cellular activation. In fact, a truncated form of RAGE, lacking only the cytosolic tail and expressed in cells, retains the binding to various ligands identically as wildtype RAGE, but does n...