LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization

Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.

Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the US, Alzheimer’s disease (AD) affects 5.8 million people. However, dementia is commonly associated with more than one neuropathology, usually AD with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a moderately extended mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (e.g., symptoms present, but normal examination), neuropsychological testing can help with a diagnosis. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing should be considered in atypical dementia cases, such as age of onset under 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients benefit from non-pharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For AD, this includes an acetylcholinesterase inhibitor such as donepezil for mild-to-severe dementia, and memantine (used alone or as an add-on therapy) for moderate-to-severe dementia. Rivastigmine is approved for the symptomatic treatment of Parkinson’s disease dementia. AD currently affects 5.8 million persons in the US, and is a common cause of dementia which is usually accompanied by other neuropathology. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both non-pharmacologic and pharmacologic approaches.