Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1-derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.

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Age related macular degeneration (AMD) is one of the leading causes of blindness in Western society. A hallmark of early stage AMD are drusen, extracellular deposits that accumulate in the outer retina. Advanced glycation endproducts (AGE) accumulate with aging and are linked to several age-related diseases such as Alzheimer's disease, osteoarthritis, atherosclerosis and AMD. AGE deposits are found in drusen and in Bruch's membrane of the eye and several studies have suggested its role in promoting oxidative stress, apoptosis and lipofuscin accumulation. Recently, complement activation and chronic inflammation have been implicated in the pathogenesis of AMD. While AGEs have been shown to promote inflammation in other diseases, whether it plays a similar role in AMD is not known. This study investigates the effects of AGE stimulation on pro- and anti-inflammatory pathways in primary culture of human retinal pigment epithelial cells (RPE). Differential gene expression studies revealed a total of 41 up- and 18 down-regulated RPE genes in response to AGE stimulation. These genes fell into three categories as assessed by gene set enrichment analysis (GSEA). The main categories were inflammation (interferon-induced, immune response) and proteasome degradation, followed by caspase signaling. Using suspension array technology, protein levels of secreted cytokines and growth factors were also examined. Anti-inflammatory cytokines including IL10, IL1ra and IL9 were all overexpressed. Pro-inflammatory cytokines including IL4, IL15 and IFN-γ were overexpressed, while other pro-inflammatory cytokines including IL8, MCP1, IP10 were underexpressed after AGE stimulation, suggesting a para-inflammation state of the RPE under these conditions. Levels of mRNA of chemokine, CXCL11, and viperin, RSAD2, were up-regulated and may play a role in driving the inflammatory response via the NF-kB and JAK-STAT pathways. CXCL11 was strongly immunoreactive and associated with drusen in the AMD eye. The pathways and novel genes identified here highlight inflammation as a key response to AGE stimulation in primary culture of human RPE, and identify chemokine CXCL11 as putative novel agent associated with the pathogenesis of AMD.

Recent studies have identified the potential for an important role for serotonin (5-HT) receptors in the developmental plasticity of the kitten visual cortex. 5-HT 2C receptors are transiently expressed in a patchy fashion in the visual cortex of kittens between 30 -80 days of age complementary to patches demarcated by cytochrome oxidase staining. 5-HT, operating via 5-HT2C receptors, increases cortical synaptic plasticity as assessed both in brain slices and in vivo. Herein, we report that bath application of 5-HT substantially increases the probability of long-term potentiation within 5-HT 2C receptor-rich zones of cortex, but this effect is not observed in the 5-HT 2C receptor-poor zones. Instead, in these zones, 5-HT application increases the probability of long-term depression. These location-specific effects of 5-HT may promote the formation of compartment-specific cortical responses. S pecific, transient, regional, laminar, and columnar changes in the distribution of neurotransmitter-specific afferents and receptors have been shown to occur during the critical period of increased visual cortex plasticity (1-4). Fig. 1 summarizes autoradiographic and histochemical studies showing that, during the critical period, the kitten visual cortex transiently expresses a number of neurochemical markers in a columnar fashion. This columnar, biochemical architecture consists of two sets of complementary columns: one set is enriched in 5-HT 2C and 5-HT 2A receptors along with synaptic zinc, whereas the other expresses increased levels of CO and acetylcholinesterase (3, 4). Among over 30 neurotransmitter receptors that have been studied within the visual cortex (1, 2), only the 5-HT receptors noted above have been found to concentrate into columns within the developing cortex.A special relationship between this 5-HT receptor system and the use-dependent plasticity of visual cortex is reinforced by studies showing that these receptor columns do not form in kittens in which one eye was removed early in life or in animals that were deprived of vision by dark rearing (1, 5). In addition, studies in developing kittens have shown that blockade of 5-HT 2C receptors with mesulergine reduces the activitydependent binocular competition that normally occurs when one eye is deprived of vision (6).Working in brain slices taken from visual cortex of 60-to 80-day-old kittens, we found that low-frequency stimulation (LFS) of the white matter (1 Hz, 15 min) rarely induced long-term potentiation (LTP) or long-term depression (LTD) in layer IV (7). At these ages, however, bath application of 5-HT markedly facilitated the induction of both LTP and LTD. The effects of 5-HT on both LTP and LTD were blocked by the 5-HT 2C antagonist mesulergine (7). Although the general effect of 5-HT application was clearly to increase the probability of long-term changes in response to electrical stimulation, we could not predict the variety of effects that were mediated by 5-HT (sometimes LTP, sometimes LTD, and sometimes no change).We hypothesized that th...