Augmentation of nicotinic ␣7 receptor function is considered to be a potential therapeutic strategy aimed at ameliorating cognitive and mnemonic dysfunction in relation to debilitating pathological conditions, such as Alzheimer's disease and schizophrenia. In the present report, a novel positive allosteric modulator of the ␣7 nicotinic acetylcholine receptor (nAChR), 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethylphenyl)-urea (NS1738), is described. NS1738 was unable to displace or affect radioligand binding to the agonist binding site of nicotinic receptors, and it was devoid of effect when applied alone in electrophysiological paradigms. However, when applied in the presence of acetylcholine (ACh), NS1738 produced a marked increase in the current flowing through ␣7 nAChRs, as determined in both oocyte electrophysiology and patchclamp recordings from mammalian cells. NS1738 acted by increasing the peak amplitude of ACh-evoked currents at all concentrations; thus, it increased the maximal efficacy of ACh. Oocyte experiments indicated an increase in ACh potency as well. NS1738 had only marginal effects on the desensitization kinetics of ␣7 nAChRs, as determined from patch-clamp studies of both transfected cells and cultured hippocampal neurons. NS1738 was modestly brain-penetrant, and it was demonstrated to counteract a (Ϫ)-scopolamine-induced deficit in acquisition of a water-maze learning task in rats. Moreover, NS1738 improved performance in the rat social recognition test to the same extent as (Ϫ)-nicotine, demonstrating that NS1738 is capable of producing cognitive enhancement in vivo. These data support the notion that ␣7 nAChR allosteric modulation may constitute a novel pharmacological principle for the treatment of cognitive dysfunction.In clinical conditions where it is desirable to augment the function of a particular receptor type, positive allosteric modulation of the receptor in question is frequently considered preferable to classical (orthosteric) agonism. This primarily relies on the fact that actions of positive allosteric modulators are use-dependent, because only receptors activated by the endogenous ligand (agonist) are subject to modulation. Therefore, the temporospatial characteristics of endogenous receptor activation are preserved, and the function of the modulator can be considered as increasing the gain of individual receptor activation events. Agonists, in contrast, tonically activate all receptors. This will lead to a nonphysiological pattern of receptor activation, and it is also well known that prolonged agonist exposure will lead to receptor desensitization and that it affects receptor expression patterns (for review, see Quick and Lester, 2002).The cysteine-loop-containing family of ligand-gated ion channels encompasses anion-preferring receptor channels for ␥-aminobutyric acid (GABA A and GABA C receptors) and glycine as well as cation-preferring receptor channels activated by 5-hydroxytryptamine (5-hydroxytryptamine 3 receptors) and acetylcholine (nicotinic r...

The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts.

BACKGROUND AND PURPOSEPositive allosteric modulation of a4b2 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 APPROACHEffects 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 RESULTSNS9283 was shown to increase agonist-evoked response amplitude of (a4)3(b2)2 nACh receptors in electrophysiology paradigms. (a2)3(b2)2, (a2)3(b4)2 and (a4)3(b4)2 were modulated to comparable extents, but no effects were detected at a3-containing or any 2a : 3b stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHbE-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 IMPLICATIONSThese results provide compelling evidence that positive allosteric modulators acting at the (a4)3(b2)2 nACh receptors can augment activity across a broad range of cognitive domains, and that a4b2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment. Abbreviations

1 Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysacharride (LPS; 5 mg kg-', i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2 The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert3 The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4 Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5 The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by N0-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The ICm for L-NAME was 2.5 t4M against the constitutive NOS from brain, and 20-25 tLM against the inducible NOS. For L-NMMA the IC50 was 20-25 AM against either NOS isoform.7 The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 1l1,9,,-epoxymethano prostaglandin F2. (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated (6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 JM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8 Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.