Chronic high-dose creatine has opposing effects on depression-related gene expression and behavior in intact and sex hormone-treated gonadectomized male and female rats.
Chronic high-dose creatine has opposing effects on depression-related gene expression and behavior in intact and sex hormone-treated gonadectomized male and female rats.
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DOI：
10.1016/j.pbb.2014.12.014
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Kanarek RB
中科院分区：
文献类型：
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作者：
Allen PJ;DeBold JF;Rios M;Kanarek RB
肌酸是一种抗氧化剂、神经调节剂和能量代谢的关键调节剂，可改善人类和动物，尤其是雌性动物的抑郁症状。为了更好地了解肌酸的药理作用，我们研究了在存在和不存在性类固醇的情况下，肌酸对抑郁相关海马基因表达和行为的影响。假手术和去性腺细胞的雄性和雌性大鼠分别饲喂单独的饲料或混合2%或4% w/w的一水肌酸的饲料5周，然后进行强迫游泳、露天场地和钢丝悬浮试验，或总共7周。在补充之前，男性长期植入一个空的或充满睾酮(T)的胶囊（10毫米表面释放），女性每周给予黄体酮（P, 250 μg），苯甲酸雌二醇（EB, 2.5 μg）， EB+P或香油载体。与未补充的假体相比，所有海马可塑性相关mrna，包括脑源性神经营养因子（BDNF）、酪氨酸激酶B、双皮质素、calretinin和calbindin，在给予4%肌酸的假体雄性中下调，在给予4%肌酸的假体雌性中下调BDNF、双皮质素和calbindin mrna。相比之下，4%肌酸+ T在阉割动物中阻止了BDNF、双皮质素和calretinin mrna的下调。同样，在切除卵巢的女性中，4%肌酸+ EB+P联合治疗可以减弱BDNF和calbindin mRNA水平的下调。在接受EB+ p治疗的去势雌性动物中观察到中度抗抑郁和焦虑样行为，在接受t治疗的去势雌性动物中也有类似的趋势。总之，这些数据表明，在完整和性腺去角质的雄性和雌性大鼠中，慢性高剂量肌酸对神经可塑性相关基因和抑郁行为具有相反的作用。使用肌酸的剂量和时间表可能通过能量代谢的负代偿变化对健康大脑的海马神经元完整性产生负面影响，而在去性腺的大鼠中，肌酸和性类固醇联合使用具有神经保护作用，可能通过减少与去势或卵巢切除术相关的代谢并发症。
Creatine is an antioxidant, neuromodulator and key regulator of energy metabolism shown to improve depressive symptoms in humans and animals, especially in females. To better understand the pharmacological effects of creatine, we examined its influence on depression-related hippocampal gene expression and behaviors in the presence and absence of sex steroids. Sham-operated and gonadectomized male and female rats were fed chow alone or chow blended with either 2% or 4% w/w creatine monohydrate for five weeks before forced swim, open field, and wire suspension tests, or seven weeks total. Before supplementation, males were chronically implanted with an empty or a testosterone-filled (T) capsule (10-mm surface release), and females were administered progesterone (P, 250 μg), estradiol benzoate (EB, 2.5 μg), EB+P, or sesame oil vehicle weekly. Relative to non-supplemented shams, all hippocampal plasticity-related mRNAs measured, including brain-derived neurotrophic factor (BDNF), tyrosine kinase B, doublecortin, calretinin, and calbindin, were downregulated in sham males given 4% creatine, and BDNF, doublecortin, and calbindin mRNAs were downregulated in sham females given 4% creatine. In contrast, combined 4% creatine + T in castrates prevented downregulation of BDNF, doublecortin, and calretinin mRNAs. Similarly, combined 4% creatine + EB+P in ovariectomized females attenuated downregulation of BDNF and calbindin mRNA levels. Moderate antidepressant and anxiolytic-like behaviors were observed in EB+P-treated ovariectomized females fed creatine, with similar trends in T-treated castrates fed creatine. Altogether, these data show that chronic, high-dose creatine has opposing effects on neuroplasticity-related genes and depressive behavior in intact and gonadectomized male and female rats. The dose and schedule of creatine used negatively impacted hippocampal neuronal integrity in otherwise healthy brains, possibly through negative compensatory changes in energy metabolism, whereas combined creatine and sex steroids acted in a neuroprotective manner in gonadectomized rats, potentially by reducing metabolic complications associated with castration or ovariectomy.