A PDK-1 allosteric agonist improves spatial learning and memory in a βAPP/PS-1 transgenic mouse-high fat diet intervention model of Alzheimer's disease.

Diabetes mellitus (DM), peripheral insulin resistance (IR) and obesity are clear risk factors for Alzheimer's disease. Several anti-diabetic drugs and insulin have been tested in rodents and humans with MCI or AD, yielding promising but inconclusive results. The PDK-1/Akt axis, essential to the action of insulin, has not however been pharmacologically interrogated to a similar degree.

Intravenously Administered Ganaxolone Blocks Diazepam-Resistant Lithium-Pilocarpine-Induced Status Epilepticus in Rats: Comparison with Allopregnanolone.

Ganaxolone (GNX) is the 3-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.

A Mouse Model of Furosemide-Induced Overactive Bladder.

Detailed in this unit is a mouse model of overactive bladder and urinary incontinence based on diuretic stress-induced urination. The procedure involves the use of a unique, highly sensitive, and automated urine capturing method to measure urinary latency, frequency, and void volume. Although this method was first described and validated using an anti-muscarinic drug used for treating overactive bladder, subsequent work has shown that effective non-cholinergic agents can be detected.

Discovery of 7-arylsulfonyl-1,2,3,4, 4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridines: identification of a potent and selective 5-HT₆ receptor antagonist showing activity in rat social recognition test.

Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists.

Novel brain penetrant benzofuropiperidine 5-HT₆ receptor antagonists.

7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.

Social recognition assay in the rat.

Neuropsychiatric disorders encompass a broad patient population in a variety of disease states across all age groups and are often accompanied by deficits in short-term/working memory. However, most preclinical models that allow for an assessment of cognitive enhancement do not provide robust behavioral readouts with a level of throughput sufficient to support modern drug discovery efforts. The rat social recognition assay presented in this unit is one exception that has been increasingly employed to test new chemical entities for enhancing cognitive activity.

Novel object recognition in the rat: a facile assay for cognitive function.

The rat novel object recognition (NOR) assay is a relatively high-throughput, robust, and sensitive procedure for evaluating compounds for cognition-enhancing activity. For the test, rats are given the opportunity to explore two identical objects for a predetermined period of time. After a delay, the animals are then presented with two objects to explore, one of which is the same as in the first exploration trial, the other a new object.

Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities.

Dimebolin (Dimebon), is a non-selective antihistamine approved in Russia for the treatment of allergy. Recently, this drug has been shown to be neuroprotective in cellular models of Alzheimer's disease and Huntington's disease, and to preserve cognitive function when chronically administered to AF64A lesioned rats. Interests in identifying the molecular targets of dimebolin have intensified with reports of efficacy in clinical trials with Alzheimer's patients.