Canagliflozin as a Neuroprotective Agent to Improve Neuroinflammation and Cognitive Function during Aging

卡格列净作为神经保护剂改善衰老过程中的神经炎症和认知功能

• 批准号: 10740151
• 负责人: Marianna Sadagurski
• 金额: $ 116.19万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740151
• 关键词: Adult; Affect; Age; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Biochemical; Brain; Brain Diseases; Brain region; Cardiovascular Diseases; Cells; Chronic Disease; Clinical; Cognitive; Collaborations; Data; Diabetes Mellitus; Disease; Disease Progression; Dose; Drug Prescriptions; Elderly; Exhibits; Exploratory Behavior; FDA approved; Family; Female; Food; Gene Expression; Gene Expression Profile; Genes; Germ Cells; Glucose Transporter; Goals; Hand Strength; Health; Heterogeneity; High Pressure Liquid Chromatography; Homeostasis; Human; Hypothalamic structure; Immune; In Vitro; Inflammasome; Inflammatory; Inflammatory Response; Insulin; Intervention; Lesion; Lipids; Long-Term Effects; Longevity; Measurement; Measures; Mediating; Mediator; Memory; Metabolic; Metabolic Control; Metabolic Pathway; Microglia; Molecular; Molecular Profiling; Motor Activity; Mus; Neurodegenerative Disorders; Neuroprotective Agents; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physical activity; Physiological; Process; Property; Quality of life; Risk Factors; Senile Plaques; Series; Sex Differences; Signal Pathway; Signal Transduction; Societies; Sodium; Testing; Translating; age related; age related neurodegeneration; aged; aging brain; attenuation; brain cell; cognitive function; cognitive performance; experimental study; frailty; genetic approach; glucose metabolism; improved; in vivo; inhibitor; male; marenostrin; mouse model; neuroinflammation; neuroprotection; novel; novel therapeutics; pharmacologic; prevent; programs; response; sex; tau Proteins; transcriptome; transcriptomics; translational impact

ABSTRACT Aging is the dominant risk factor for most chronic diseases including neurodegenerative diseases. There is now ample evidence, in mice, that the process of aging can be delayed by pharmacological compounds that target numerous cellular and molecular pathways that have been implicated in the aging process and also delay multiple forms of late-life illness, including Alzheimer's disease (AD). In collaboration with the Intervention Testing Program (ITP), we have recently demonstrated that an FDA-approved anti-diabetes drug, Canagliflozin (Cana), a sodium- glucose transporter 2 (SGLT2) inhibitor, extended the lifespan in the genetically diverse UM-HET3 male mice by 14%, without an effect on females. The question of whether Cana has beneficial effects on the aging brain or amelioration of age-associated diseases in the brain remains open. Our new study demonstrated that Cana exhibits neuroprotective properties, such as improved central insulin responsiveness and reduced region-specific neuroinflammation. Furthermore, Cana treatment improved locomotor activity and exploratory behavior in aged male mice. Our preliminary data further reveal significant changes in hypothalamic transcriptome associated with decreased expression of genes related to activation of inflammatory responses specifically genes related to NLRP3 inflammasome activation in aged Cana-treated mice. Our central hypothesis is that Cana exhibits neuroprotective properties that may be applicable for the treatment of the aging brain and/or neurodegenerative diseases. This hypothesis will be assessed using genetically diverse UM-HET3 mice fed with Cana from 7 months of age and followed longitudinally by combining physiological, molecular, and genetic approaches. We will determine the effects of Cana treatment on cognitive function during aging and correlate this with the measurements of Cana levels in the brain. We will assess the Cana effect on microglia inflammasome activation and study brain spatial transcriptomic changes in aged mice to identify key pathways/genes mediating the pharmacological effects of Cana. Finally, we will determine the effects of Cana on cognitive performance using two well-established mice models of AD, 5xFAD and PS19 Tau. Our study has the potential to test the pharmacological effects of an established drug on cognitive degeneration in aging, as well as to identify novel cellular and molecular mechanisms underlying this pharmacological effect. Taken together, our study will validate Cana as a drug that can be rapidly used for preventing or treating AD in humans.

抽象的 衰老是大多数包括神经退行性疾病在内的大多数慢性疾病的主要危险因素。 现在有充分的证据在小鼠中，可以延迟衰老的过程 靶向众多细胞和分子途径的药理化合物 与衰老过程有关，还延迟了多种形式的晚期疾病，包括 阿尔茨海默氏病（AD）。与干预测试计划（ITP）合作，我们有 最近证明了FDA批准的抗糖尿病药物Canagliflozin（Cana），一种钠 葡萄糖转运蛋白2（SGLT2）抑制剂延长了遗传多样的UM-HET3中的寿命 雄性小鼠的14％，对女性没有影响。 Cana是否有益的问题 对大脑衰老的大脑衰老的影响仍然开放。 我们的新研究表明，CANA具有神经保护特性，例如改善 中央胰岛素反应性和降低区域特异性神经炎症。此外，Cana 治疗改善了老年雄性小鼠的运动活性和探索行为。我们的初步 数据进一步揭示了与减少相关的下丘脑转录组的显着变化 与炎症反应激活有关的基因的表达，特异性基因 老年CANA处理的小鼠的NLRP3炎性体激活。我们的中心假设是 表现出可能适用于治疗衰老脑的神经保护特性 和/或神经退行性疾病。该假设将使用遗传多样性评估 UM-HET3小鼠用7个月大的CANA喂食，然后通过合并来纵向 生理，分子和遗传方法。我们将确定CANA治疗的影响 关于衰老期间的认知功能，并将其与CANA水平的测量 脑。我们将评估CANA对小胶质细胞炎症体激活的影响并研究脑空间 老年小鼠的转录组变化，以识别介导的关键途径/基因 CANA的药理作用。最后，我们将确定CANA对认知的影响 使用两种良好的AD小鼠模型，5XFAD和PS19 TAU的性能。我们的研究有 测试已建立药物对认知变性的药理作用的潜力 在衰老中，以及确定这一点的新型细胞和分子机制 药理效应。综上所述，我们的研究将验证CANA作为可以迅速的药物 用于预防或治疗人类广告。