Pharmacological Characterization of Memoquin, a Multi-Target Compound for the Treatment of Alzheimer's Disease

<div><p>Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, <i>in vivo</i> behavioral studies with MQ have been limited. Here, we report on <i>in vivo</i> studies with MQ (acute and sub-chronic treatments; 7–15 mg/kg <i>per os</i>) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aβ-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.</p> </div

Functional Properties of a Newly Identified C-terminal Splice Variant of Ca(v)1.3 L-type Ca2+ Channels

An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within theCterminus of long Ca(v)1.3 L-type Ca2+ channels (Cav1.3(L)) is a major determinant of their voltage-and Ca2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Ca(v)1.3(42A) channels that activate at a more negative voltage range and exhibit more pronounced Ca2+-dependent inactivation. Here we describe the discovery of a novel short splice variant (Ca(v)1.3(43S)) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Ca(v)1.3(42A), still contains PCRD. When expressed together with alpha 2 delta 1 and beta 3 subunits in tsA-201 cells, Ca(v)1.3(43S) also activated at more negative voltages like Ca(v)1.3(42A) but Ca2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Ca(v)1.3(L). The presence of the proximal C terminus in Ca(v)1.3(43S) channels preserved their modulation by distal C terminus-containing Ca(v)1.3- and Ca(v)1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca2+ influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Ca(v)1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca2+ channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca2+ accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca2+-induced neurodegenerative processes

REVIEW OF X-RAY LASER RESEARCH AT CEL-V

International audienc

REVIEW OF X-RAY LASER RESEARCH AT CEL-V

Nous présentons l'état actuel des travaux relatifs au laser X réalisés avec le laser Octal. Les résultats récents concernant les inversions de populations pouvant conduire à une amplification sont rapportés. La théorie et les modèles impliqués dans les schémas d'inversion seront examinés.We present the status of X-ray laser experiments using the Octal laser facility. Recent results dealing with population inversion towards X-ray amplification are reported. Theory and modelling of the involved schemes will also be discussed