The Causal Role of Magnesium Deficiency in the Neuroinflammation, Pain Hypersensitivity and Memory/Emotional Deficits in Ovariectomized and Aged Female Mice.
The Causal Role of Magnesium Deficiency in the Neuroinflammation, Pain Hypersensitivity and Memory/Emotional Deficits in Ovariectomized and Aged Female Mice.
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DOI：
10.2147/jir.s330894
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发表时间：
2021
影响因子：
4.5
通讯作者：
Liu XG
中科院分区：
文献类型：
--
作者：
Zhang J;Mai CL;Xiong Y;Lin ZJ;Jie YT;Mai JZ;Liu C;Xie MX;Zhou X;Liu XG
绝经后女性常遭受慢性疼痛、记忆力减退和情绪抑郁等问题。目前，导致这些神经功能紊乱的机制尚未完全明晰，且仍缺乏有效的治疗方法。
研究人员对L - 苏糖酸镁口服给药治疗去卵巢及老龄雌性小鼠神经功能紊乱的效果进行了测试。通过一系列行为测试来衡量小鼠的痛觉过敏、记忆功能以及类似抑郁的行为。同时，利用蛋白质免疫印迹法、免疫化学和原位杂交技术来评估分子变化。
长期口服L - 苏糖酸镁能显著预防或逆转去卵巢及老龄雌性小鼠的慢性疼痛以及记忆/情感缺陷。研究发现，在去卵巢及老龄小鼠的背根神经节、脊髓背角和海马体神经元中，核因子 - κB的活性形式——磷酸化p65、肿瘤坏死因子 - α以及白细胞介素 - 1β均显著上调。脊髓背角和海马体中的小胶质细胞和星形胶质细胞被激活。降钙素基因相关肽（一种肽能C纤维的标志物）在背角中上调，这与模型小鼠中C纤维介导的突触传递增强有关。与神经炎症和突触增强同时出现的是，血浆、脑脊液以及背根神经节神经元中的游离Mg²⁺水平显著降低。口服L - 苏糖酸镁可使神经炎症、突触增强和Mg²⁺缺乏恢复正常，但并不影响去卵巢及老龄小鼠体内雌激素水平的下降。此外，在培养的背根神经节神经元中，生理浓度的雌激素仅在细胞外存在Mg²⁺的情况下，才会升高细胞内Mg²⁺水平，并下调磷酸化p65、肿瘤坏死因子 - α和白细胞介素 - 1β。
绝经后雌激素水平下降可能通过降低神经元内的细胞内Mg²⁺引发神经炎症，进而导致慢性疼痛、记忆/情感缺陷。通过口服L - 苏糖酸镁补充Mg²⁺，可能是治疗与绝经相关神经功能紊乱的一种新方法。
Postmenopausal women often suffer from chronic pain, memory decline and mood depression. The mechanisms underlying the neuronal disorders are not fully understood, and effective treatment is still lacking. Oral administration of magnesium-L-threonate was tested to treat the neuronal disorders in ovariectomized and aged female mice. The pain hypersensitivity, memory function and depression-like behaviors were measured with a set of behavioral tests. Western blots, immunochemistry and in situ hybridization were used to assess molecular changes. Chronic oral administration of magnesium-L-threonate substantially prevented or reversed the chronic pain and memory/emotional deficits in both ovariectomized and aged female mice. We found that phospho-p65, an active form of nuclear factor-kappaB, tumor necrosis factor-alpha and interleukin-1 beta were significantly upregulated in the neurons of dorsal root ganglion, spinal dorsal horn and hippocampus in ovariectomized and aged mice. The microglia and astrocytes were activated in spinal dorsal horn and hippocampus. Calcitonin gene–related peptide, a marker for peptidergic C-fibers, was upregulated in dorsal horn, which is associated with potentiation of C-fiber-mediated synaptic transmission in the model mice. In parallel with neuroinflammation and synaptic potentiation, free Mg2+ levels in plasma, cerebrospinal fluid and in dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg2+ deficiency, but did not affect the estrogen decline in ovariectomized and aged mice. Furthermore, in cultured dorsal root ganglion neurons, estrogen at physiological concentration elevated intracellular Mg2+, and downregulated phospho-p65, tumor necrosis factor-alpha and interleukin-1 beta exclusively in the presence of extracellular Mg2+. Estrogen decline in menopause may cause neuroinflammation by reducing intracellular Mg2+ in neurons, leading to chronic pain, memory/emotional deficits. Supplement Mg2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.