PDF(Pubmed)
Abstract：
Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide possesses well-demonstrated antioxidant, anti-inflammatory, and anti-aggregation properties, and it may be useful for treatment of pathologies characterized by oxidative stress and energy unbalance such as depression and Alzheimer\'s disease (AD). Microglia, the brain-resident macrophages, are involved in different physiological brain activities such synaptic plasticity and neurogenesis, but their dysregulation has been linked to the pathogenesis of numerous diseases. In AD brain, the activation of microglia towards a pro-oxidant and pro-inflammatory phenotype has found in an early phase of cognitive decline, reason why new pharmacological targets related to microglia activation are of great importance to develop innovative therapeutic strategies. In particular, microglia represent a common model of lipopolysaccharides (LPS)-induced activation to identify novel pharmacological targets for depression and AD and numerous studies have linked the impairment of energy metabolism, including ATP dyshomeostasis, to the onset of depressive episodes. In the present study, we first investigated the toxic potential of LPS + ATP in the absence or presence of carnosine. Our studies were carried out on human microglia (HMC3 cell line) in which LPS + ATP combination has shown the ability to promote cell death, oxidative stress, and inflammation. Additionally, to shed more light on the molecular mechanisms underlying the protective effect of carnosine, its ability to modulate reactive oxygen species production and the variation of parameters representative of cellular energy metabolism was evaluated by microchip electrophoresis coupled to laser-induced fluorescence and high performance liquid chromatography, respectively. In our experimental conditions, carnosine prevented LPS + ATP-induced cell death and oxidative stress, also completely restoring basal energy metabolism in human HMC3 microglia. Our results suggest a therapeutic potential of carnosine as a new pharmacological tool in the context of multifactorial disorders characterize by neuroinflammatory phenomena including depression and AD.
摘要：
肌肽(β-丙氨酰-L-组氨酸)是广泛分布在可兴奋组织如脑中的天然存在的内源性肽。这种二肽具有良好的抗氧化剂，抗炎,和反聚集属性，它可用于治疗以氧化应激和能量失衡为特征的病理，如抑郁症和阿尔茨海默病（AD）。小胶质细胞,大脑驻留的巨噬细胞，参与不同的生理大脑活动，如突触可塑性和神经发生，但是它们的失调与许多疾病的发病机理有关。在AD大脑中，在认知衰退的早期阶段发现了小胶质细胞向促氧化和促炎表型的激活，与小胶质细胞激活相关的新药理靶点对于开发创新治疗策略非常重要。特别是,小胶质细胞代表了脂多糖（LPS）诱导激活的常见模型，以确定抑郁症和AD的新药理靶标，并且许多研究已经将能量代谢的损害联系起来。包括ATP代谢紊乱,抑郁发作的开始。在本研究中,我们首先研究了在不存在或存在肌肽的情况下LPS+ATP的毒性潜力。我们的研究是在人小胶质细胞（HMC3细胞系）上进行的，其中LPS+ATP组合显示出促进细胞死亡的能力，氧化应激，和炎症。此外,为了进一步阐明肌肽保护作用的分子机制，通过微芯片电泳结合激光诱导荧光和高效液相色谱法评估了其调节活性氧产生和代表细胞能量代谢参数变化的能力，分别。在我们的实验条件下，肌肽可预防LPS+ATP诱导的细胞死亡和氧化应激，也完全恢复了人类HMC3小胶质细胞的基础能量代谢。我们的结果表明，在以包括抑郁症和AD在内的神经炎现象为特征的多因素疾病中，肌肽作为一种新的药理学工具具有治疗潜力。
