Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.

BACKGROUND AND PURPOSE: Positive allosteric modulation of α4ß2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively. EXPERIMENTAL APPROACH: Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+) imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats. KEY RESULTS: NS9283 was shown to increase agonist-evoked response amplitude of (α4)(3) (ß2)(2) nACh receptors in electrophysiology paradigms. (α2)(3) (ß2)(2) , (α2)(3) (ß4)(2) and (α4)(3) (ß4)(2) were modulated to comparable extents, but no effects were detected at α3-containing or any 2α : 3ß stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHßE-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors. CONCLUSIONS AND IMPLICATIONS: These results provide compelling evidence that positive allosteric modulators acting at the (α4)(3) (ß2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that α4ß2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.

Translating clinical activity and gene expression signatures of etanercept and ciclosporin to the psoriasis xenograft SCID mouse model.

BACKGROUND: The psoriasis xenograft severe combined immunodeficiency (SCID) mouse model is used in drug discovery to obtain preclinical proof-of-principle of new antipsoriatic drug candidates. Validation of this model by antipsoriatic therapeutic agents in clinical use is important to understand its utility as well as its limitations. The effects of the clinically efficacious antitumour necrosis factor-α biologics have not yet been demonstrated in the psoriasis xenograft SCID mouse model. OBJECTIVES: To investigate the effect of etanercept and to explore the time-dependent changes induced by ciclosporin on psoriatic biomarkers at the gene expression level in the psoriasis xenograft SCID mouse model. METHODS: Xenografted SCID mice were treated either with etanercept and vehicle for 2 weeks or with ciclosporin and vehicle for 2 and 4 weeks, respectively. Treatment-induced changes in the psoriatic grafts were assessed by gene expression analysis and compared with published clinical microarray data. The grafts were further evaluated by histology and immunohistochemistry. RESULTS: Etanercept induced normalization of gene expression, which correlated with a significant reduction in epidermal thickness as well as a decrease in the number of proliferative cells. Anti-inflammatory activity induced by ciclosporin preceded the reduction in epidermal hyperplasia. Comparison of the etanercept- and ciclosporin-induced gene expression signatures with clinical microarray data showed significant correlations. CONCLUSIONS: Efficacy of etanercept and ciclosporin could be translated to the psoriasis xenograft SCID mouse model.

Prospective study of cataract surgery, capsulotomy, and retinal detachment.

We report the incidence of retinal detachment (RD) in 1543 consecutive cases of cataract extraction in a prospective cohort study. Retinal detachment was significantly associated with intracapsular extraction, axial lengths of 24.0 mm or longer and an intact capsule, and capsulotomy in eyes with axial lengths of 24.0 mm or longer. The interval between capsulotomy and RD was significantly shorter in eyes with axial lengths of 24.0 mm or greater. An intraocular lens with stiff, vaulted, poly(methyl methacrylate) optics and a biconvex PMMA optic was associated with significantly less capsule opacification than lenses of other designs.