GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.

Temporal change in gene expression in the rat dentate gyrus following passive avoidance learning.

A learning event initiates a cascade of altered gene expression leading to synaptic remodelling within the hippocampal dentate gyrus, a structure vital to memory formation. To illuminate this transcriptional program of synaptic plasticity we used microarrays to quantify mRNA from the rat dentate gyrus at increasing times following passive avoidance learning. Approximately, 500 known genes were transcriptionally regulated across the 24 h post-training period.

Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.

Design and synthesis of novel isoquinoline-3-nitriles as orally bioavailable Kv1.5 antagonists for the treatment of atrial fibrillation.

Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, IKur.

SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models.

SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and 9.

Relationship of vascular risk to the progression of Alzheimer disease.

Objective: To test the hypothesis that patients with Alzheimer disease (AD) who have vascular risk factors have a worse prognosis over 18 months vs those without such risk factors.

Methods: A sample of 224 people with AD and their caregivers were recruited purposively to be representative of people with dementia in terms of cognition, sex, and living situations in a longitudinal study of AD. Standardized instruments measuring cognition, functional status, and neuropsychiatric symptoms were used to collect data.

Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides.

This letter describes the discovery of a novel series of potent Kv1.5 ion channel antagonists based on a diisopropyl amide scaffold. Structure-activity relationships of functionalized analogs are discussed.

Adherence to treatment in mood disorders.

Purpose Of Review: Nonadherence to medication is common in mood disorders. Improving adherence should decrease risk of relapse, improve outcome and lessen costs. Here we review recent qualitative and quantitative work in this area.

Block of peripheral nerve sodium channels selectively inhibits features of neuropathic pain in rats.

Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2'-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N'-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker.

Administrative registers in psychiatric research: a systematic review of validity studies.

Objective: To conduct a systematic review of studies investigating the validity of administrative registers for use in psychiatric research.

Method: Studies were identified using MEDLINE (1966-2004) and EMBASE (1980-2004) databases using keywords 'validity' or 'reliability' combined with 'register' or 'database$'. Studies reviewed by two raters blind to each other and quality assessed using a data extraction form devised by the authors.

In vivo cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker, (2-Isopropyl-5-methylcyclohexyl) diphenylphosphine oxide, in rat and nonhuman primate.

The voltage-gated potassium channel, Kv1.5, which underlies the ultrarapid delayed rectifier current, I(Kur), is reported to be enriched in human atrium versus ventricle, and has been proposed as a target for novel atrial antiarrhythmic therapy. The administration of the novel I(Kur) blocker (2-isopropyl-5-methyl-cyclohexyl) diphenylphosphine oxide (DPO-1) (0.

Amyloid precursor protein expression in the rat hippocampal dentate gyrus modulates during memory consolidation.

Despite advances in our understanding of the basic biology of amyloid precursor protein (APP), the normal physiological function(s) of APP in learning and memory remains unclear. Here we show increased APP degradation in the hippocampus to be associated with the consolidation of a passive avoidance response. Neurone-specific APP695 expression became transiently reduced 2-4 h post-training through association with endosomal adaptin proteins and enhanced internalization.

Complex-environment rearing prevents prenatal hypoxia-induced deficits in hippocampal cellular mechanisms necessary for memory consolidation in the adult Wistar rat.

Hypoxic episodes in utero can result in enduring and debilitating neurological sequelae that include nonprogressive motor disorders and/or significant learning deficits. The extent of long-term disruption of synaptic function following prenatal hypoxia and its subsequent effect on learning ability, however, remain to be established. Polysialylation of the neural cell adhesion molecule, a cellular event integral to the consolidation of diverse learning paradigms, was used to correlate cellular end points with learning deficits as a consequence of prenatal hypoxia.

Anxiety and depression in family caregivers of people with Alzheimer disease: the LASER-AD study.

Objective: There are high rates of stress, distress, and psychological illness in family caregivers of people with dementia. Female caregivers and those caring for people with neuropsychiatric symptoms are particularly at risk. The authors report on the prevalence of anxiety and depression in a sample of family caregivers of people with Alzheimer disease (AD) and compare the characteristics of those who did or did not have those conditions.

Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing.

Novel method to assess cardiac electrophysiology in the rat: characterization of standard ion channel blockers.

The rat continues to be an important tool to assess cardiac electrophysiologic (EP) effects of test agents and to study the distribution/role of ion channels in cardiovascular diseases. However, no data have been described that accurately measure discrete cardiac EP parameters in rats in vivo. Therefore, we developed a method to assess cardiac EP in rats and then profiled several ion channel agents.

Structure-activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists.

SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.

Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core.

Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.

The Caregivers for Alzheimer's disease Problems Scale (CAPS): development of a new scale within the LASER-AD study.

Background: we developed the Caregivers for Alzheimer's disease Problems Scale (CAPS) comprising common risk factors for anxiety and depression for family carers of people with dementia.

Objective: to calculate the sensitivity and specificity of the CAPS in order to measure its usefulness in identifying dementia caregivers at risk of anxiety and depression and therefore whether it identifies clinically relevant areas for intervention or highlights the need for support if the problem could not be changed.

Method: 153 family caregivers were interviewed as part of a larger epidemiologically representative study of people with Alzheimer's disease and their caregivers.

Relationship of exercise and other risk factors to depression of Alzheimer's disease: the LASER-AD study.

Background: Depression is common in Alzheimer's disease (AD; 5-35%). It is associated with increased disability, cost of care and carer burden. Exercise is known to be associated with a lower prevalence of depression across the age range but little is known about its relationship to depression in AD.

Increased incidence of postoperative cognitive dysfunction 24 hr after minor surgery in the elderly.

Purpose: Postoperative cognitive dysfunction (POCD) is evident in 26% of elderly patients seven days after major non-cardiac surgery. Despite the growing popularity of day surgery, the influence of anesthetic techniques on next day POCD has not been investigated. Therefore, we evaluated the incidence of POCD and changes in serum markers of neuronal damage (S-100ss protein and Neuron-Specific Enolase), 24 hr after single-agent propofol or sevoflurane anesthesia in elderly patients undergoing minor surgery.

Identification of a peptide binding motif for secreted frizzled-related protein-1.

Secreted Frizzled-related proteins (sFRPs) bind Wnts and modulate their activity. To identify putative sFRP-1 binding motifs, we screened an M13 phage displayed combinatorial peptide library. A predominant motif, L/V-VDGRW-L/V, was present in approximately 70% of the phage that bound sFRP-1.

Neurobiological and endocrine correlates of individual differences in spatial learning ability.

The polysialylated neural cell adhesion molecule (PSA-NCAM) has been implicated in activity-dependent synaptic remodeling and memory formation. Here, we questioned whether training-induced modulation of PSA-NCAM expression might be related to individual differences in spatial learning abilities. At 12 h posttraining, immunohistochemical analyses revealed a learning-induced up-regulation of PSA-NCAM in the hippocampal dentate gyrus that was related to the spatial learning abilities displayed by rats during training.