Beyond retigabine: Design, identification, and pharmacological characterization of novel neuronal Kv7 channel activators

The Kv7 subfamily of voltage-gated potassium channels includes 5 members (Kv7.1-Kv7.5) having distinct expression patterns and physiological roles. Kv7.2 and Kv7.3 subunits are mainly expressed in the nervous system, where they underlie the so-called M-current (IKM), a sub-threshold K+ current controlling action potential generation. Neuronal Kv7 potassium channels are critical regulators of neuronal excitability; indeed, loss-of-function mutations in the genes encoding for Kv7.2 and Kv7.3 are responsible for a wide spectrum of early-onset epilepsies. On the other hand, retigabine is a strong activator of the Kv7 currents, representing the first antiepileptic drug acting on Kv7 channels. Approved in 2011 for adjunctive therapy in adults showing drug-resistant partial onset seizures with or without secondary generalization, retigabine suppresses neuronal hyperexcitability by shifting the Kv7.2/3 current activation threshold toward more hyperpolarized potentials, thereby increasing their maximal current. Unfortunately, retigabine, suffers from considerable drawbacks including poor selectivity for Kv7 subtypes, short half-life, poor brain penetration and chemical instability. The latter, represents one of the main clinical concern over retigabine; light exposure may cause photodegradation and oxidation, leading to dimer formation, which induces retinal and mucocutaneous blue-gray discoloration in patients taking the drugs more than 3 years. For these reasons, leading to a progressively reduced use of the drug, the manufacturing company (GSK) has decided to withdraw the drug from the market since June 2017. Since no KCNQ activator is currently available for clinical use, this work originates from our effort to identify novel and safer IKM activators. For this purpose, we synthesized a library of 41 retigabine derivatives, structurally characterized by modification that aim to overcome at least some of the limitations of retigabine and we developed a fluorescence-based assay to rapidly evaluate the effect of these derivatives on Kv7 channel

A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy

OBJECTIVE: Heterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability. METHODS: Exome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits. RESULTS: A novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits. SIGNIFICANCE: The present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities

Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor

Cardiac fibrosis is implicit in all forms of heart disease but there are no effective treatments. In this report, we investigate the role of the multi-functional enzyme Transglutaminase 2 (TG2) in cardiac fibrosis and assess its potential as a therapeutic target. Here we describe the use a highly selective TG2 small-molecule inhibitor to test the efficacy of TG2 inhibition as an anti-fibrotic therapy for heart failure employing two different in vivo models of cardiac fibrosis: Progressively induced interstitial cardiac fibrosis by pressure overload using angiotensin II infusion: Acutely induced focal cardiac fibrosis through myocardial infarction by ligation of the left anterior descending coronary artery (AMI model). In the AMI model, in vivo MRI showed that the TG2 inhibitor 1–155 significantly reduced infarct size by over 50% and reduced post-infarct remodelling at 20 days post insult. In both models, Sirius red staining for collagen deposition and levels of the TG2-mediated protein crosslink ε(γ-glutamyl)lysine were significantly reduced. No cardiac rupture or obvious signs of toxicity were observed. To provide a molecular mechanism for TG2 involvement in cardiac fibrosis, we show that both TGFβ1-induced transition of cardiofibroblasts into myofibroblast-like cells and TGFβ1- induced EndMT, together with matrix deposition, can be attenuated by the TG2 selective inhibitor 1–155, suggesting a new role for TG2 in regulating TGFβ1 signalling in addition to its role in latent TGFβ1 activation. In conclusion, TG2 has a role in cardiac fibrosis through activation of myofibroblasts and matrix deposition. TG2 inhibition using a selective small-molecule inhibitor can attenuate cardiac fibrosis

Theano - Iliade VI 297-312 : mise en scène d'une prière entre gestes et paroles

Piera Nappi Maria. Theano - Iliade VI 297-312 : mise en scène d'une prière entre gestes et paroles. In: Anatolia Antiqua, Tome 14, 2006. pp. 159-170

Sylvie Perceau, La parole vive. Communiquer en catalogue dans l'épopée homérique

Nappi Maria Piera. Sylvie Perceau, La parole vive. Communiquer en catalogue dans l'épopée homérique. In: Gaia : revue interdisciplinaire sur la Grèce Archaïque, numéro 9, 2005. pp. 241-244

Sylvie Perceau, La parole vive. Communiquer en catalogue dans l'épopée homérique

Nappi Maria Piera. Sylvie Perceau, La parole vive. Communiquer en catalogue dans l'épopée homérique. In: Gaia : revue interdisciplinaire sur la Grèce Archaïque, numéro 9, 2005. pp. 241-244

Value creation and the impact of corporate real estate assets

PurposeThe purpose of this paper is to investigate the impact of corporate real estate (CRE) ownership on value creation for non‐financial French listed companies.Design/methodology/approachUsing a pool sample composed of SBF 250 companies over the period 1999‐2004, this paper investigates the association between economic value added (EVA) and market value added (MVA) as proxies for the value generated by French listed companies and the proportion of real estate in their asset portfolio.FindingsThe empirical results show that an increase in the proportion of real estate assets (over total assets) is negatively associated with EVA, but only for firms in service industries exhibiting low real estate intensity. The regression on MVA shows a negative association with the increase in the proportion of real estate for firms outside the service industries.Research limitations/implicationsRecent trends show that many large companies have sold a significant portion of their CRE assets. The underlying motives for such behaviour are yet to be examined (at least for the French context). If real estate has any influence, an association should be observable between proxies of value creation and the change in the proportion of real estate assets, owned by a company. The results suggest that sales of CRE assets may be driven by value maximizing behaviour.Practical implicationsIn order to maximize the value of their firm, managers should apparently take value creation into consideration in their decisions to invest in or dispose of real estate assets.Originality/valueThe paper suggests that in a French context, CRE disposals may generate value added in certain industries with specific CRE intensity.</jats:sec