Allen Patricia J, DeBold Joseph F, Rios Maribel, Kanarek Robin B
Department of Psychology, Tufts University, Medford, MA 02155, USA.
Department of Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Pharmacol Biochem Behav. 2015 Mar;130:22-33. doi: 10.1016/j.pbb.2014.12.014. Epub 2015 Jan 3.
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.
肌酸是一种抗氧化剂、神经调节剂和能量代谢的关键调节因子，已被证明可改善人类和动物，尤其是雌性动物的抑郁症状。为了更好地理解肌酸的药理作用，我们研究了在有和没有性类固醇的情况下，肌酸对与抑郁相关的海马基因表达和行为的影响。在进行强迫游泳、旷场和悬尾试验前5周，或总共7周，对假手术和去势的雄性和雌性大鼠单独喂食普通饲料或与2%或4%（w/w）一水肌酸混合的饲料。在补充肌酸之前，雄性大鼠长期植入空胶囊或填充睾酮（T）的胶囊（10毫米表面释放），雌性大鼠每周注射孕酮（P，250μg）、苯甲酸雌二醇（EB，2.5μg）、EB+P或芝麻油载体。相对于未补充肌酸的假手术组，在给予4%肌酸的假手术雄性大鼠中，所有检测的与海马可塑性相关的mRNA，包括脑源性神经营养因子（BDNF）、酪氨酸激酶B、双皮质素、钙视网膜蛋白和钙结合蛋白，均下调；在给予4%肌酸的假手术雌性大鼠中，BDNF、双皮质素和钙结合蛋白mRNA下调。相比之下，去势大鼠中4%肌酸+T联合使用可防止BDNF、双皮质素和钙视网膜蛋白mRNA的下调。同样，在去卵巢雌性大鼠中，4%肌酸+EB+P联合使用可减弱BDNF和钙结合蛋白mRNA水平的下调。在喂食肌酸的经EB+P处理的去卵巢雌性大鼠中观察到中度抗抑郁和抗焦虑样行为，在喂食肌酸的经T处理的去势大鼠中也有类似趋势。总之，这些数据表明，长期高剂量肌酸对完整和去势的雄性和雌性大鼠中与神经可塑性相关的基因和抑郁行为有相反的影响。所使用的肌酸剂量和给药方案对原本健康的大脑中的海马神经元完整性产生负面影响，可能是通过能量代谢的负性代偿性变化，而肌酸和性类固醇联合使用在去势大鼠中具有神经保护作用，可能是通过减少与去势或卵巢切除相关的代谢并发症。
