Salmeterol, a \u3b22 Adrenergic Agonist, Promotes Adult Hippocampal Neurogenesis in a Region-Specific Manner.

Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (\u3b2-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of \u3b22-AR by norepinephrine and \u3b22-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective \u3b22-AR agonist able to cross the blood-brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult na\uefve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior

Pharmacological rationale for tapentadol therapy: a review of new evidence

Chronic pain could be considered as a neurological disorder. Therefore, appropriate selection of the therapy, which should consider the pathophysiological mechanisms of pain, can result in a successful analgesic outcome. Tapentadol is an analgesic drug which acts both as a μ-opioid receptor (MOR) agonist and as a noradrenaline reuptake inhibitor (NRI), thereby generating a synergistic action in terms of analgesic efficacy, but not for the burden of adverse effects. Therefore, tapentadol can be defined as the first “MOR-NRI” drug. This molecule holds the potential to address at least some of the current limitations of analgesic therapy due to its unique mechanism of action and has shown to be safe and effective in the treatment of chronic pain of cancer and noncancer etiologies including nociceptive, neuropathic and mixed pain. In particular, the MOR component of tapentadol activity predominantly allows for analgesia in nociceptive pain; on the other hand, the NRI component contributes, now in a predominant manner, for analgesic efficacy in cases of neuropathic pain states. This paper will discuss recent pieces of evidence on the pathophysiology of pain, the background on tapentadol and then present some new studies on how the unique mechanism of action of tapentadol provides a key role in its analgesic efficacy in a number of pain states and with a favorable safety profile

Diagnostic accuracy of HLA-B*5701 screening for the prediction of abacavir hypersensitivity and clinical utility of the test: a meta-analytic review

Aims: This study was conducted to determine the diagnostic accuracy of HLA-B*5701 testing for prediction of abacavir-induced hypersensitivity (ABC-HSR) and to quantify the clinical benefit of pre-treatment screening through a meta-analytic review of published studies. Materials and methods: A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model. Results: Pooled analysis showed that HLA-B*5701 test specificity is about 97-98%, regardless of the use of clinical criteria or of skin patch test for the diagnosis of abacavir-induced hypersensitivity. Conversely, the use of the patch test to immunologically confirm the clinical diagnosis of ABC-HSR improves sensitivity of the test from 40% to 98%. Pooled analysis of risk ratio (RR) and risk difference (RD) showed that prospective HLA-B*5701 testing significantly reduced the incidence of abacavir-induced hypersensitivity. Conclusions: The results of this meta-analysis demonstrated an excellent diagnostic accuracy of HLA-B*5071 testing to detect IC-HSR and corroborated existing recommendations for HLA-B*5701 screening before initiation of abacavir-containing therapy