Neuroscience
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Potassium channels play an important role in microglial activation but their involvement in main functions of microglia including secretion of proinflammatory cytokines has remained uncertain. This study has revealed the specific expression of Kv1.1 in microglia both in vivo and in vitro. Kv1.1 immunoreactivity was localized in the amoeboid microglia in the rat brain between postnatal (P) day 1 (P1) and day 10 (P10); it was, however, progressively reduced with age and was hardly detected at P14 and P21 in ramified microglia, a derivative cell of amoeboid microglia. ⋯ RT-PCR and Western blot analysis confirmed Kv1.1 mRNA and protein expression in murine BV-2 cells which was up-regulated by hypoxia or lipopolysaccharide (LPS) treatment; it was reduced significantly by dexamethasone. Neutralization with Kv1.1 antibody suppressed the expression and release of tumor necrosis factor-alpha, interleukin-1beta, endothelins and nitric oxide (NO) in LPS-activated BV-2 cells. It is concluded that Kv1.1, constitutively expressed by microglia, is elicited by hypoxia and LPS and this may be linked to production of proinflammatory cytokines, endothelins and NO.
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Sex differences in water maze performance and cortical neurotrophin levels of LHX7 null mutant mice.
Mice lacking both alleles of the LIM-homeobox gene Lhx7 display dramatically reduced number of forebrain cholinergic neurons. Given the fact that sex differences are consistently observed in forebrain cholinergic function, in the present study we investigated whether the absence of LHX7 differentially affects water maze performance in the two sexes. ⋯ Nevertheless, the compensatory increase of cortical neurotrophin levels did not restore cognitive abilities of Lhx7 homozygous mutants. Finally, our analysis revealed that cortical neurotrophin levels correlate negatively with water maze proficiency, indicating that there is an optimal neurotrophin level for successful cognitive performance.
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Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. ⋯ There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.
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Activation of the complement system occurs in a variety of neuroinflammatory diseases and neurodegenerative processes of the CNS. Studies in the last decade have demonstrated that essentially all of the activation components and receptors of the complement system are produced by astrocytes, microglia, and neurons. There is also rapidly growing evidence to indicate an active role of the complement system in cerebral ischemic injury. ⋯ Intravenous immunoglobulin (IVIG) has the potential to inhibit multiple components of inflammation, including complement fragments, pro-inflammatory cytokine production and leukocyte cell adhesion. Thus, IVIG may directly protect neurons, reduce activation of intrinsic inflammatory cells (microglia) and inhibit transendothelial infiltration of leukocytes into the brain parenchyma following an ischemic stroke. The striking neuroprotective actions of IVIG in animal models of ischemic stroke suggest a potential therapeutic potential that merits consideration for clinical trials in stroke patients.
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Extensive evidence implicates inflammation in multiple phases of stroke etiology and pathology. In particular, there is growing awareness that inflammatory events outside the brain have an important impact on stroke susceptibility and outcome. ⋯ Here, we provide an overview of the impact of systemic inflammation on stroke susceptibility and outcome. We discuss potential mechanisms underlying the impact on ischemic brain injury and highlight the implications for stroke prevention, therapy and modeling.