Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-α, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-α on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-α is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-α is now known to cause transient increases in intracellular Ca2+ levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca2+ homeostasis could be involved. Ryanodine was found to significantly reverse the inhibition of LTP by TNF-α. From these studies we propose that the TNF-α inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca2+ stores in TNF-α mediated inhibition of LTP

Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation

<p>Abstract</p> <p>Objectives</p> <p>The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation.</p> <p>Methods</p> <p>The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs.</p> <p>Results</p> <p>MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009).</p> <p>Conclusion</p> <p>In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.</p

A conceptual governance framework for climate change adaptation and disaster risk reduction integration

Climate change adaptation (CCA) and disaster risk reduction (DRR) have similar targets and goals in relation to climate change and related risks. The integration of CCA in core DRR operations is crucial to provide simultaneous benefits for social systems coping with challenges posed by climate extremes and climate change. Although state actors are generally responsible for governing a public issue such as CCA and DRR integration, the reform of top-down governing modes in neoliberal societies has enlarged the range of potential actors to include non state actors from economic and social communities. These new intervening actors require in-depth investigation. To achieve this goal, the article investigates the set of actors and their bridging arrangements that create and shape governance in CCA and DRR integration. The article conducts a comprehensive literature review in order to retrieve main actors and arrangements. The article summarizes actors and arrangements into a conceptual governance framework that can be used as a backdrop for future research on the topic. However, this framework has an explorative form, which must be refined according to site- and context-specific variables, norms, or networks. Accordingly, this article promotes an initial application of the framework to different contexts. Scholars may adopt the framework as a roadmap with which to corroborate the existence of a theoretical and empirical body of knowledge on governance of CCA and DRR integration

Pacific island regional preparedness for El Niño

The El Niño Southern Oscillation (ENSO) cycle is often blamed for disasters in Pacific island communities. From a disaster risk reduction (DRR) perspective, the challenges with the El Niño part of the ENSO cycle, in particular, are more related to inadequate vulnerability reduction within development than to ENSO-induced hazard influences. This paper analyses this situation, filling in a conceptual and geographic gap in El Niño-related research, by reviewing El Niño-related preparedness (the conceptual gap) for Pacific islands (the geographic gap). Through exploring El Niño impacts on Pacific island communities alongside their vulnerabilities, resiliences, and preparedness with respect to El Niño, El Niño is seen as a constructed discourse rather than as a damaging phenomenon, leading to suggestions for El Niño preparedness as DRR as part of development. Yet the attention which El Niño garners might bring resources to the Pacific region and its development needs, albeit in the short term while El Niño lasts. Conversely, the attention given to El Niño could shift blame from underlying causes of vulnerability to a hazard-centric viewpoint. Instead of focusing on one hazard-influencing phenomenon, opportunities should be created for the Pacific region to tackle wider DRR and development concerns