piperidines and 3-(2-4-dimethoxybenzylidene)anabaseine

Experiments on random-bred albino mice showed that M1 muscarinic acetylcholine receptor agonist (TBPB) and α7n-acetylcholine receptor agonist (GTS-21) significantly reduced mortality of mice with experimental sepsis (intraperitoneally administration of E. coli) in 4 and 24 h after modeling by reducing blood concentration of proinflammatory cytokines TNF-α, IL-1β, and IL-6. Combined treatment with TBPB and GTS-21 determined their additive effect.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzimidazoles; Benzylidene Compounds; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Female; Gene Expression Regulation; Interleukin-1beta; Interleukin-6; Male; Mice; Muscarinic Agonists; Nicotinic Agonists; Piperidines; Pyridines; Receptor, Muscarinic M1; Sepsis; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

The cognitive deficits associated with schizophrenia are recognized as a core component of the disorder, yet there remain no available therapeutics to treat these symptoms of the disease. As a result, there is a need for establishing predictive preclinical models to identify the therapeutic potential of novel compounds. In the present study, rhesus monkeys were trained in the object retrieval-detour task, which is dependent on the prefrontal cortex, a brain region implicated in the cognitive deficits associated with schizophrenia. The NMDA receptor antagonist ketamine significantly impaired performance without affecting measures of motor or visuospatial abilities. Pre-treatment with the nicotinic α7 agonist GTS-21 (0.03 mg/kg) significantly attenuated the ketamine-induced impairment, consistent with reports from clinical trials suggesting that nicotinic α7 receptor agonism has pro-cognitive potential in clinical populations. In contrast, pretreatment with the acetylcholinesterase inhibitor donepezil failed to reverse the ketamine-induced impairment, consistent with studies showing a lack of pro-cognitive effects in patients with schizophrenia. These data suggest that the ketamine-impaired object retrieval-detour task could provide a model with improved predictive validity for drug development, and confirm the need for additional efforts in back-translation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Benzylidene Compounds; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Indans; Ketamine; Macaca mulatta; Male; Molecular Targeted Therapy; Nicotinic Agonists; Nootropic Agents; Piperidines; Psychomotor Performance; Pyridines; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Schizophrenia