Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation.

BACKGROUND AND PURPOSE: Bones are widely innervated, suggesting an important role for the sympathetic regulation of bone metabolism, although there are controversial studies. We investigated the effects of propranolol in a model of experimental periodontal disease. EXPERIMENTAL APPROACH: Rats were assigned as follows: animals without ligature; ligated animals receiving vehicle and ligated animals receiving 0.1, 5 or 20 mg·kg(-1) propranolol. After 30 days, haemodynamic parameters were measured by cardiac catheterization. Gingival tissues were removed and assessed for IL-1ß, TNF-α and cross-linked carboxyterminal telopeptides of type I collagen (CTX) by elisa, or intercellular adhesion molecule 1 (ICAM-1), receptor activator of NF-κ B ligand (RANKL) and osteoprotegerin (OPG) by Western blot analysis. Sections from the mandibles were evaluated for bone resorption. Also, we analysed the ability of propranolol to inhibit osteoclastogenesis in vitro. RESULTS: Propranolol at 0.1 and 5 mg·kg(-1) reduced the bone resorption as well as ICAM-1 and RANKL expression. However, only 0.1 mg·kg(-1) reduced IL-1ß, TNF-α and CTX levels as well as increased the expression of OPG, but did not alter any of the haemodynamic parameters. Propranolol also suppressed in vitro osteoclast differentiation and resorptive activity by inhibiting the nuclear factor of activated T cells (NFATc)1 pathway and the expression of tartrate-resistant acid phosphatase (TRAP), cathepsin K and MMP-9. CONCLUSIONS AND IMPLICATIONS: Low doses of propranolol suppress bone resorption by inhibiting RANKL-mediated osteoclastogenesis as well as inflammatory markers without affecting haemodynamic parameters.

Reconsolidation or extinction: transcription factor switch in the determination of memory course after retrieval.

In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-κB (NF-κB) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-κB and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-κB enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.

[Safety of topical tacrolimus and pimecrolimus in children with atopic dermatitis]. / Inocuidad de tacrolimus y pimecrolimus tópicos en niños con dermatitis atópica.

The use of topical immunomodulators in pediatric patients is an important topic in the clinical practice. Their prescription for chronic diseases suggests the necessity of evaluating their efficacy and safety profile in a long term period. In children they can develop systemic adverse events after their application, though sometimes they are useful to reduce the long consumption of other drugs, as topical steroids, or to have influence in the critical aspects of immunomodulation. Pimecrolimus and tacrolimus are two topical calcineurin inhibitors, from which there are several reports that support their efficacy in pediatric patients with atopic dermatitis. Recently, the FDA issued a recommendation for their topical use in a sporadic way in two years old children or older that have moderate to serious atopic dermatitis and that have not responded to other treatments. This article shows the results of several studies in which these drugs have been applied for a long time in children with atopic dermatitis. The more frequent adverse effects were: infections, pyrexia, burning, pruritus, erythema, and papules in the application area. In suckling babies they were: dry skin, pruritus, infections, constipation, erythema, and papules. Even when these adverse effects have been reported with relative frequency, their controlled use in concrete clinical conditions is still a therapeutic option and they should be considered particularly useful in the treatment of atopic dermatitis without positive reaction to other treatments in children older than two years, during short periods and in cases in which immunocompromised situations have been ruled out.