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Cotinine for Cognitive Impairment in Neurological and Neuropsychiatric Disorders

可替宁治疗神经和神经精神疾病的认知障碍

基本信息

批准号：
7874475
负责人：
ALVIN V TERRY
金额：
$ 29.24万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7874475
关键词：
Acetylcholine Address Affect Age-Months Alzheimer&apos s Disease Amyloid Animals Antipsychotic Agents Attention Attention deficit hyperactivity disorder Attenuated Behavior Behavioral Blood Pressure Brain Brain region Breathing Cells Cerebrum Choline Chronic Clinical Clinical Trials Cognition Cognitive deficits Cotinine Development Disease Dose Effectiveness Environmental Tobacco Smoke Exhibits Experimental Designs Food Hallucinogens Impaired cognition In Vitro Incubated Institution Light MK801 Macaca mulatta Mediating Memory Memory impairment Mental disorders Methods Modeling Monkeys Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Nicotine Nicotinic Receptors Performance Perfusion Pharmaceutical Preparations Pharmacology Phase Play Population Preparation Procedures Property Rattus Reaction Time Relative (related person)Research Research Design Research Personnel Rest Rodent Rodent Model Role Sampling Schizophrenia Screening procedure Short-Term Memory Symptoms Synaptosomes Therapeutic Therapeutic Agents Tobacco Tobacco use Training Transgenic Mice Transgenic Organisms Vesicle analog awake base behavior test brain tissue cholinergic neuron cognitive function cytotoxic desensitization design drinking water human disease improved meetings model design mouse model neuroprotection neuropsychiatry neurotoxicity nicotine replacement nonhuman primate novel programs receptor receptor expression relating to nervous system research study smoking cessation therapeutic target translational approach transmission process

项目摘要

DESCRIPTION (provided by applicant): In recent years our research findings have provided a new appreciation for the potential pharmacological properties of cotinine, the principal metabolite of nicotine produced after using tobacco products. We now provide compelling evidence that cotinine is indeed a pharmacologically active compound having a number of actions that suggest that it might mediate some of the beneficial effects of nicotine, as well as exhibiting some unique properties of its own. Cotinine was shown to have full efficacy (relative to nicotine) in protecting neural-like cells in culture from a cytotoxic insult. The drug was active in a rat model that predicts antipsychotic-like potential. Cotinine also improved working memory accuracy by non-human primates, and the drug exhibited ability to enhance attention in a distractor version of the same task. Finally we demonstrated that unlike nicotine, cotinine failed to stimulate autonomic ganglionic transmission in the awake rat, but it partly desensitized ganglionic receptors without affecting resting blood pressure. We propose to extend these findings by studying the potential neuroprotective properties of cotinine in a transgenic mouse model of Alzheimer's disease. The potential of cotinine as a prototypical agent to improve cognition in schizophrenia will be studied in a rat model of sustained attention and in monkeys in a working memory task by evaluating the ability of the compound to attenuate or reverse the impairing effects of low doses of psychotomimetic agents. Finally, the relative ability of cotinine to desensitize nicotinic receptors will be determined in of acetylcholine release from relevant regions of rat and monkey CNS. We expect at the completion of these studies to show that cotinine has exploitable therapeutic potential relevant to human diseases that feature behavioral and cognitive impairment and neurodegeneration. Based on its cognition-enhancing and antipsychotic potential, cotinine also could prove useful in the difficult to treat cognitive deficits associated with schizophrenia. Perhaps even more importantly cotinine has the potential to serve as a prototypical agent by which new drug entities may be compared. The partly translational design of the study will provide results leading to eventual clinical trials with cotinine or a relevant analog.

描述（由申请人提供）：近年来，我们的研究结果为可替宁（使用烟草产品后产生的尼古丁的主要代谢产物）的潜在药理学特性提供了新的认识。我们现在提供了令人信服的证据，证明可替宁确实是一种具有多种作用的尼古丁活性化合物，表明它可能介导尼古丁的一些有益作用，并表现出其自身的一些独特特性。可替宁显示出在保护培养物中的神经样细胞免受细胞毒性损伤方面具有完全功效（相对于尼古丁）。该药物在预测抗精神病样潜力的大鼠模型中具有活性。可替宁还提高了非人类灵长类动物的工作记忆准确性，并且该药物在相同任务的分心版本中表现出增强注意力的能力。最后，我们证明，与尼古丁不同，可替宁未能刺激清醒大鼠的自主神经节传递，但它部分脱敏神经节受体，而不影响静息血压。我们建议通过研究可替宁在阿尔茨海默病转基因小鼠模型中的潜在神经保护特性来扩展这些发现。将在大鼠持续注意力模型和猴工作记忆任务中，通过评价化合物减弱或逆转低剂量拟精神病药物损害作用的能力，研究可替宁作为原型药物改善精神分裂症认知的潜力。最后，可替宁使烟碱受体脱敏的相对能力将在大鼠和猴CNS相关区域的乙酰胆碱释放中确定。我们希望在完成这些研究时，表明可替宁具有与人类疾病相关的可开发的治疗潜力，这些疾病的特征是行为和认知障碍以及神经变性。基于其认知增强和抗精神病的潜力，可替宁也可能被证明对难以治疗的与精神分裂症相关的认知缺陷有用。也许更重要的是，可替宁有可能作为一种原型药物，通过它可以比较新药实体。该研究的部分转化设计将提供导致可替宁或相关类似物最终临床试验的结果。