Mechanisms Underlying Sex-Specific Effects of Creatine Supplementation on Depress

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能量平衡的关键调节器，以抗抑郁的方式发挥作用。研究表明，补充肌酸可以显著改善难治性抑郁症患者的情绪，并假设肌酸改变大脑化学物质的方式增加了对抗抑郁药物治疗的反应的可能性。在过去的两年里，我们的实验室一直在使用强迫游泳试验积极研究长期补充肌酸对大鼠抑郁样行为的影响。强迫游泳试验是一种动物模型，对改变人类抑郁症状的药物具有选择性敏感性。重要的是，这些研究表明，长期补充肌酸会导致抑郁样行为中可靠的性别改变(Allen等人，2009年)。具体地说，肌酸在女性身上产生类似抗抑郁的作用，在男性身上产生促进抑郁的作用。这些发现支持了Renshaw等人(2001)的报告，即改变抑郁症女性的嘌呤水平与治疗反应有关，而不是男性。深入了解这些影响的机制具有重要的临床意义，因为在人类抑郁症的患病率和治疗方面的性别差异已被广泛报道。初步研究表明，肌酸在女性体内的抗抑郁作用可能是通过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备消耗的酶。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例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影响在缺乏卵巢或睾丸激素的情况下是否能够持续。第二个目的是研究肌酸和神经营养相关的神经元活动之间是否存在联系。有证据表明，肌酸和脑源性神经营养因子(BDNF)有许多共同的性质，BDNF是突触可塑性的基本媒介，与抑郁症密切相关。脑源性神经营养因子与性腺类固醇激素有多种相互作用，可能是肌酸引起抑郁行为改变的分子机制之一。如果性腺类固醇操作后性别依赖的行为表型仍然存在，则计划进行研究，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影响。推测雌激素介导肌酸的抗抑郁作用，肌酸和脑源性神经营养因子在雄性和雌性大鼠中的表达存在差异。激素和神经营养变量与肌酸和行为的检验是新颖的，这些研究的生化数据将有助于阐明肌酸行为影响的潜在机制。总之，这些研究将填补有关补充肌酸对抑郁行为的性二态、神经和行为后果的关键知识空白。 公共卫生相关性：鉴于肌酸在大脑中日益增长的功能和临床意义，有必要更充分地表征这种物质在情绪障碍的病理生理学中的作用。此外，研究肌酸治疗对大鼠抑郁样行为的性别差异的潜在机制将深刻影响我们对肌酸及其与抑郁行为的关系的理解，并可能导致针对性别的治疗策略。这项研究与公众健康利益高度相关，因为肌酸是迄今为止使用最广泛的营养补充剂之一，肌酸改变情绪的潜力可能直接影响抑郁症的治疗。

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.