These data show that a calorie-restricted KD enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores.
Cyclooxygenase-2 (COX-2), a source of inflammatory mediators and a multifunctional neuronal modulator, is rapidly induced in select populations of cortical neurons after status epilepticus. The consequences of rapid activity-triggered induction of COX-2 in neurons have been the subject of much study and speculation. To address this issue directly, we created a mouse in which COX-2 is conditionally ablated in selected forebrain neurons. Results following pilocarpine-induced status epilepticus indicate that neuronal COX-2 promotes early neuroprotection and then delayed neurodegeneration of CA1 pyramidal neurons, promotes neurodegeneration of nearby somatostatin interneurons in the CA1 stratum oriens and dentate hilus (which themselves do not express COX-2), intensifies a broad inflammatory reaction involving numerous cytokines and other inflammatory mediators in the hippocampus, and is essential for development of a leaky blood–brain barrier after seizures. These findings point to a profound role of seizure-induced neuronal COX-2 expression in neuropathologies that accompany epileptogenesis.
Activation of the Gαs-coupled EP2 receptor for prostaglandin E2 (PGE 2 ) promotes cell survival in several models of tissue damage. To advance understanding of EP2 functions, we designed experiments to develop allosteric potentiators of this key prostaglandin receptor. Screens of 292,000 compounds identified 93 that at 20 μM (i) potentiated the cAMP response to a low concentration of PGE 2 by > 50%; (ii) had no effect on EP4 or β2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE 2 on EP2 receptors at least 3-fold. In aqueous solution, the active compounds are largely present as nanoparticles that appear to serve as active reservoirs for bioactive monomer. From 94 compounds synthesized or purchased, based on the modification of one hit compound, the most active increased the potency of PGE 2 on EP2 receptors 4-to 5-fold at 10 to 20 μM and showed substantial neuroprotection in an excitotoxicity model. These small molecules represent previously undescribed allosteric modulators of a PGE 2 receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE 2 released in a cell-injury setting is neuroprotective.excitotoxicity | neuronal injury | prostaglandin E2 | time-resolved fluorescence resonance energy transfer | ultra high-throughput screening C yclooxygenase-2 (COX2), which is constitutively expressed at low to moderate levels in both neuronal cell bodies and dendritic spines in the hippocampus, is regulated by synaptic activity (1) and is rapidly induced in neurons after a seizure (2) or cerebral ischemia (3,4). Studies in rodents have demonstrated that COX2 activation by ischemia or status epilepticus generally contributes to neuronal injury (5-8), but multiple downstream COX2 signaling pathways suggest that the mechanisms promoting and opposing brain injury are complex. Among the enzymatic products of COX2 is prostaglandin E2 (PGE 2 ), which can activate four G protein-coupled receptors (GPCRs): EP1, EP2, EP3, and EP4. Activation of the EP2 receptor by PGE 2 appears to be neuroprotective after ischemia (3, 4), whereas EP1 activation promotes neurodegeneration (8). The yin-yang nature of the PGE 2 receptor family demonstrates the value of a neuroprotection strategy involving modulation of a specific prostanoid receptor rather than generic block of the entire COX2 signaling cascade.EP2 is a Gαs-coupled receptor that, when activated by PGE 2 , stimulates adenylate cyclase, resulting in elevation of cytoplasmic cAMP (cAMP) level. In addition to its suspected neuroprotective role, EP2 activation has also been shown to promote spatial learning (9), to improve survival of epithelial cells after radiation injury (10), to accelerate bone healing after fracture (11), and to improve renal function in a HgCl 2 model of chronic renal failure (12). On the other hand, EP2 activation in microglia could promote inflammation and neurotoxicity in some neurodegenerative disease models, such as Alzheimer's disease and amyotrophic late...
Double‐stranded RNA (dsRNA) induces the vascular cell adhesion molecule VCAM‐1 to high levels of expression in human umbilical vein endothelial (HUVE) cells. Although VCAM‐1 is also induced by the cytokine interleukin 1β (IL‐1β), activation of the dsRNA‐activated protein kinase (PKR) occurs only in response to incubation with dsRNA but not with IL‐1β. Incubation of HUVE cells with the synthetic dsRNA, poly (I) · poly (C), activates PKR with increased autophosphorylation, increased phosphorylation of the translation factor eIF2α, and increased activation of the transcription factor NF‐кB. Promoter analysis in HUVE cells using a VCAM‐1 promoter linked to CAT reporter gene demonstrates that poly (I) · poly (C) responsiveness resides in the minimal VCAM‐1 promoter that contains two NF‐кB sites, and deletion of the NF‐кB sites eliminates basal and poly (I) · poly (C)‐induced CAT activity, supporting the importance of NF‐кB in the poly (I) · poly (C)‐mediated induction of VCAM‐1. In vitro studies using purified reagents demonstrate that PKR is capable of phosphorylating IкBα (the inhibitory subunit of NF‐кB) in a dsRNA‐dependent manner. This suggests that phosphorylation of IкBα by PKR could be an initial step in the activation of NF‐кB by dsRNA. NF‐кB is also activated by IL‐1β in HUVE cells, but this activation occurs without increased PKR autophosphorylation or eIF2α phosphorylation. Poly (I) · poly (C) induces VCAM‐1 mRNA levels that are dramatically higher and sustained longer than levels induced by IL‐1β. Although phosphorylation of eIF2α interferes with protein translation, sufficient VCAM‐1 mRNA translation occurs in response to poly (I) · poly (C) to yield VCAM‐1 protein levels that are similar to levels that are induced by IL‐1bT. This suggests that the higher, sustained VCAM‐1 mRNA levels that occur in response to incubation with poly (I) · poly (C) compensate for the partial translational block resulting from increased eIF2α phosphorylation. These studies indicate that transcrip‐tional and translational regulatory events that occur in response to activation of PKR by dsRNA are important in the regulation of VCAM‐1 gene expression in HUVE cells.
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