Investigation of the neurochemical, molecular and behavioural properties of the putative lithium-mimetic, ebselen

Lithium is the first choice drug for the treatment of bipolar disorder and it is also used as supplementary therapy for treatment-resistant depression. A leading candidate target of lithium is inositol monophosphatase (IMPase) which is critically involved in signalling via the phosphoinositide cycle (PI). Ebselen, first developed as an anti-inflammatory and anti-oxidant drug, has recently been shown to inhibit IMPase and therefore is a putative lithium-mimetic. This project aimed to investigate the neuropharmacological effects of ebselen in mouse models relevant to depression. Initial studies examined the function of 5-HT2A and 5-HT2C receptors, which signal through PI cycle. Ebselen attenuated the responses of systemically administered 5-HT2A agonists at the behavioural and molecular level; specifically the induction of head twitches and ear scratches and increased immediate early gene (IEG) expression. Lithium produced similar effects to ebselen in the same experiments. In addition, an IMPase inhibitor but not a GSK-3 inhibitor mimicked the effect of ebselen at the behavioural model of 5-HT2A receptor function. Ebselen also reduced 5-HT2C receptor function, as assessed using IEG expression, and lithium had a similar effect. Ebselen was also found to increase 5-HT synthesis in mouse brain regions as previously reported for lithium. In microdialysis studies, ebselen tended to enhance the increase in extracellular 5-HT levels induced by the SSRI citalopram in hippocampus. This finding was consistent with the observation that ebselen and citalopram increased IEG-expression when administered together but not when administered separately. Lastly, ebselen when administered repeatedly increased the abundance of a variety of gene markers of neuronal plasticity in mouse brain regions. Lithium also increased the abundance of markers of neuronal plasticity. Overall, the present study found that ebselen attenuated 5-HT2 receptor function and partially augmented the effects of citalopram, while it increased markers of neuronal plasticity. These effects of ebselen were largely mimicked by lithium. These findings show that ebselen has similar neuropharmacological effects to lithium across a range of mouse models relevant to depression. The antidepressant potential of ebselen is discussed.</p

Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation

Purpose: Glioblastoma (GBM) is the most common type of adult brain tumor with extremely poor survival. Cystathionine-gamma lyase (CTH) is one of the main Hydrogen Sulfide (H2S) producing enzymes and its expression contributes to tumorigenesis and angiogenesis but its role in glioblastoma development remains poorly understood. Methods: and Principal Results: An established allogenic immunocompetent in vivo GBM model was used in C57BL/6J WT and CTH KO mice where the tumor volume and tumor microvessel density were blindly measured by stereological analysis. Tumor macrophage and stemness markers were measured by blinded immunohistochemistry. Mouse and human GBM cell lines were used for cell-based analyses. In human gliomas, the CTH expression was analyzed by bioinformatic analysis on different databases.In vivo, the genetic ablation of CTH in the host led to a significant reduction of the tumor volume and the protumorigenic and stemness transcription factor sex determining region Y-box 2 (SOX2). The tumor microvessel density (indicative of angiogenesis) and the expression levels of peritumoral macrophages showed no significant changes between the two genotypes. Bioinformatic analysis in human glioma tumors revealed that higher CTH expression is positively correlated to SOX2 expression and associated with worse overall survival in all grades of gliomas. Patients not responding to temozolomide have also higher CTH expression. In mouse or human GBM cells, pharmacological inhibition (PAG) or CTH knockdown (siRNA) attenuates GBM cell proliferation, migration and stem cell formation frequency. Major Conclusions: Inhibition of CTH could be a new promising target against glioblastoma formation

Amantadine Variants Activity Against Multiple Influenza A Viruses

Future pandemic influenza necessitates the development of new drugs against the current circulating, amantadine and rimantadine drugs resistant, influenza A M2 S31N viruses. The possibility of an antigenic shift to M2 S31 necessitates ranking the biological activities of amantadine variants. Several amantadine variants have been tested by different laboratories, but various M2 wild type influenza A strains have been used with different sensitivity against amantadine and the unambiguous comparison between potencies is not straightforward. Here, we compared the anti-influenza activities of 57 synthetic amantadine variants against influenza A WSN/33 viruses with amantadine-sensitive M2 WT, with a range of over three digits providing a reference set of potencies for structure-activity relationships, and amantadine-resistant M2 S31N proteins (and observed no potent compounds). 17 compounds were selected and tested against M2 L26F, V27A, A30T, G34E viruses. We tested few reference compounds using electrophysiology and explored point mutations which both showed that M2 is the target of potent antiviral potency against the M2 WT, L26F, V27A viruses. Major findings are: (a) Several amantadine variants from Kolocouris group block only M2 WT and M2 L26F-mediated proton current and the corresponding viruses replication. (b) A compound from Vazquez’s group is a triple blocker of M2 WT, L26F, V27A channels and viruses replication. (c) A compound from Vazquez’s group blocks only M2 L26 channel and virus replication. (d) Several compounds from Kolocouris group have potent activity against several influenza A M2 WT and three M2 S31N viruses, eg. the pandemic A/H1N1/California/07/2009 (H1N1pdm09) or A/H1N1/PuertoRico/08/1934 without blocking M2 S31N. The compounds and their cocktails while not to be more toxic than amantadine might be useful for re-purposing of amantadine class of drugs in the case (i) of the prevalence of M2 L26F and or M2 V27A strains (ii) of an antigenic shift of the virus to M2 WT and (iii) because they inhibited a broad panel of M2 WT and M2 S31N viruses including the H1N1pdm09). (d) We showed that the mechanism of antiviral activity against A/California/07/2009 or A/PR/08/1934 and possibly also M2 WT viruses compared to WSN/33 viruses is not due to inhibition of an early stage of virus infection or a late stage of M2 channel function during endocytosis or inhibition of HA binding to host cells or a different pH for HA fusion or a lysosomotropic effect