Genotoxic evaluation of morphine, buprenorphine, pentazocine, and noscapine by micronucleus and comet assay in albino mice

Objectives: The present study was planned to explore the genotoxicity of morphine, buprenorphine, pentazocine, and noscapine. Materials and Methods: Bone marrow micronucleus assay and single cell gel electrophoresis assay were employed after 24 h (single dose) and 72 h (three doses) of treatment with clinically equivalent doses of opioids in albino mice. Percentage of micronucleated polychromatic erythrocytes and comet tail length were determined and the results were analyzed by one-way ANOVA and Student′s ′t′ test. Results: Only morphine and noscapine showed significant (P < 0.01) increase in both the number of micronucleated polychromatic erythrocytes and comet tail lengths in acute (24-h) as well as subacute (72-h) studies. Conclusions: These results clearly indicate the genotoxic potential of morphine and noscapine at the clinically equivalent doses

WNT signaling in activated microglia is proinflammatory

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WNT Signaling in Activated Microglia Is Proinflammatory

Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased beta-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimer's disease. We substantiate disease-associated beta-catenin signaling in microglia in vivo by showing age-dependent b-catenin accumulation in mice with Alzheimer's-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize beta-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with down-stream activation of disheveled, beta-catenin stabilization, and nuclear import. Gene-expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor a. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of beta-catenin-signaling networks in this cell type. (C) 2010 Wiley-Liss, Inc