Mechanisms Underlying Sex-Specific Effects of Creatine Supplementation on Depress

肌酸补充剂对抑郁症的性别特异性影响的机制

• 批准号: 7999758
• 负责人: Patricia Joan Allen
• 金额: $ 4.24万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999758
• 关键词: Affect; Animal Model; Antidepressive Agents; Behavior; Behavioral; Biochemical; Brain; Brain Chemistry; Brain-Derived Neurotrophic Factor; Chronic; Clinical; Consumption; Creatine; Creatine Kinase; Data; Depressed mood; Enzymes; Estrogens; Female; Functional disorder; Gonadal Steroid Hormones; Homeostasis; Hormonal; Hormones; Human; Knowledge; Lead; Link; Mediating; Mediator of activation protein; Mental Depression; Molecular; Mood Disorders; Moods; Muscle; Neurons; Ovarian; Phenotype; Prevalence; Public Health; Purines; Rattus; Reporting; Research; Resistance; Role; Sex Characteristics; Supplementation; Swimming; Synaptic plasticity; Testicular Hormones; Testing; Therapeutic; Time; Woman; Work; brain tissue; clinically significant; depressive symptoms; dietary supplements; improved; insight; interest; male; men; novel; public health relevance; purine; relating to nervous system; response; sex; treatment response

DESCRIPTION (provided by applicant): Growing evidence supports the potential for creatine, a critical regulator of energy homeostasis in muscle and brain tissue, to function in an antidepressant manner. Studies indicate that creatine supplementation can significantly improve mood in treatment resistant depression, and it is hypothesized that creatine alters brain chemistry in a manner that increases the likelihood of response to antidepressant treatment. Over the last two years, our lab has been actively studying the effects of chronic creatine supplementation on depression-like behavior in rats using the forced swim test, an animal model that is selectively sensitive to agents that alter depressive symptoms in humans. Importantly, these studies show that long-term supplementation with creatine results in reliable sex-specific alterations in depression-like behavior (Allen et al, 2009). Specifically, creatine produces antidepressant-like effects in females and pro-depressant effects in males. These findings are supportive of the report by Renshaw et al (2001) that altered purine levels in depressed women, but not men, are associated with treatment response. Insight into the mechanisms underlying these effects is of great clinical importance as sex differences in the prevalence and treatment of depression in humans are widely reported. Preliminary research suggests the antidepressant-like effect of creatine in females may be explained by the phosphorylating action of estrogens or estrogenic metabolites upon creatine kinase, an enzyme that stimulates the consumption of brain energy stores. The primary aim of the present research is to determine whether the sex-specific effects of creatine supplementation on depression-like behavior are attributable to the actions of gonadal steroids at the time of forced swim testing using classic hormone manipulation paradigms. That is, this work will assess whether the effects of creatine can endure in the absence of ovarian or testicular hormones. A secondary aim is to examine whether there is a relationship between creatine and neurotrophic- related neuronal activity. Evidence points to a number of shared qualities among creatine and brain-derived neurotrophic factor (BDNF), an essential mediator of synaptic plasticity that is robustly linked with depression. BDNF diversely interacts with gonadal steroids and may be one molecular mechanism involved in the creatine- induced alterations in depressive behavior. If sex-dependent behavioral phenotypes persist after gonadal steroid manipulation, studies are planned to assess the organizational effects of sex hormones on depressive responsivity in male and female rats supplemented with creatine. It is hypothesized that estrogens mediate the antidepressant effects of creatine, and that creatine and BDNF are differentially expressed in male and female rats. The examination of hormonal and neurotrophic variables with creatine and behavior is novel, and the biochemical data from these studies will be valuable in elucidating the underlying mechanism of creatine's behavioral effects. Together these studies will fill critical gaps in knowledge regarding the sexually dimorphic neural and behavioral consequences of creatine supplementation on depressive behavior. PUBLIC HEALTH RELEVANCE: Given the mounting functional and clinical significance of creatine in the brain, it is essential to more fully characterize the role of this agent in the pathophysiology of mood disorders. Moreover, examining mechanisms underlying sex differences in depression-like behavior in rats in response to creatine treatment will profoundly affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. This research is highly relevant to public health interests, as creatine is among the most extensively used nutritional supplements to date and the potential for creatine to alter mood may directly impact management of depression.

描述（由申请人提供）：越来越多的证据支持肌酸的潜力，肌酸是肌肉和脑组织中能量稳态的关键调节剂，具有抗抑郁作用。研究表明，补充肌酸可以显著改善治疗难治性抑郁症患者的情绪，并且假设肌酸在某种程度上改变了大脑化学物质，从而增加了对抗抑郁药物治疗的反应。在过去的两年里，我们的实验室一直在积极研究慢性肌酸补充剂对大鼠抑郁样行为的影响，使用强迫游泳试验，一种对改变人类抑郁症状的药物选择性敏感的动物模型。重要的是，这些研究表明长期补充肌酸会导致抑郁样行为的性别特异性改变（Allen et al, 2009）。具体来说，肌酸对女性产生类似抗抑郁的作用，对男性产生促抑郁作用。这些发现支持了Renshaw等人（2001）的报告，即女性抑郁症患者嘌呤水平的改变与治疗效果有关，而男性则没有。深入了解这些影响的机制具有重要的临床意义，因为人类抑郁症患病率和治疗的性别差异被广泛报道。初步研究表明，女性肌酸的抗抑郁作用可能是由雌激素或雌激素代谢物对肌酸激酶的磷酸化作用来解释的，肌酸激酶是一种刺激大脑能量储存消耗的酶。本研究的主要目的是确定补充肌酸对抑郁样行为的性别特异性影响是否归因于使用经典激素操纵范式进行强迫游泳测试时性腺类固醇的作用。也就是说，这项工作将评估肌酸的作用是否能在缺乏卵巢或睾丸激素的情况下持续下去。第二个目的是检查肌酸与神经营养相关的神经元活动之间是否存在关系。有证据表明，肌酸和脑源性神经营养因子（BDNF）之间有许多共同的特性，BDNF是突触可塑性的重要介质，与抑郁症密切相关。BDNF与性腺类固醇相互作用，可能是肌酸诱导抑郁行为改变的一种分子机制。如果性腺类固醇操纵后性别依赖的行为表型持续存在，研究计划评估性激素对补充肌酸的雄性和雌性大鼠抑郁反应的组织效应。据推测，雌激素介导了肌酸的抗抑郁作用，而肌酸和BDNF在雄性和雌性大鼠中的表达是不同的。检查激素和神经营养变量与肌酸和行为是新颖的，从这些研究中得到的生化数据将有助于阐明肌酸行为影响的潜在机制。总之，这些研究将填补关于补充肌酸对抑郁行为的两性二态神经和行为后果的知识的关键空白。