A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder

IF 4.3 2区 医学 Q1 NEUROSCIENCES
Barbara J. Mason , David Estey , Amanda Roberts , Giordano de Guglielmo , Olivier George , John Light , Mike Stoolmiller , Susan Quello , Michael Skinner , Farhad Shadan , Adnan Begovic , Mark C. Kyle , R. Adron Harris
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Abstract

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Abstract Image

Abstract Image

关于 PPAR-α 激动剂在与酒精使用障碍有关的人类和啮齿动物模型中疗效的逆向转化研究
酒精使用障碍(AUD)是一种慢性复发性疾病,影响着全球约 2.83 亿人,对健康和经济造成严重后果。临床前研究显示,过氧化物酶体增殖激活受体(PPAR),尤其是 PPAR-α 和 PPAR-γ,有望成为 AUD 的潜在治疗靶点。在这项人体实验室研究中,我们的目的是将 PPAR-α 激动剂非诺贝特的临床前研究结果应用于目前患有 AUD 的人群。我们假设,相对于安慰剂,美国食品药品管理局批准的最高剂量(145 毫克/天)的非诺贝特将在实验室中减弱对体内酒精线索的反应,并在自然条件下减少饮酒。然而,研究结果并未显示非诺贝特组和安慰剂组在渴求和饮酒量方面存在显著差异。在啮齿类动物模型中进行的反向转化研究证实,非诺贝特在人体同等剂量下缺乏效果。这些研究结果表明,从啮齿动物到人类的药物剂量转化不足可能是非诺贝特对AUD患者的酒精渴求和饮酒缺乏影响的原因。这些结果突显了需要新的脑穿透性PPAR-α激动剂来充分测试PPAR-α激动剂对AUD的治疗潜力,以及逆向转化方法和选择人体等效剂量在药物开发中的重要性。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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