Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-α/NF-κB Signaling in Rats
Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-α/NF-κB Signaling in Rats
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长期口服 L-苏糖酸镁可通过大鼠 TNF-α/NF-κB 信号正常化来预防奥沙利铂引起的记忆和情绪缺陷
DOI：
10.1007/s12264-020-00563-x
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发表时间：
2020-08
影响因子：
5.6
通讯作者：
Liu Xianguo
中科院分区：
文献类型：
--
作者：
Zhou Xin;Huang Zhuo;Zhang Jun;Chen Jialiang;Yao Peiwen;Mai Chunlin;Mai Jiezhen;Zhang Hui;Liu Xianguo
抗抑郁药如奥沙利铂（OXA）经常引起记忆和情绪障碍。目前，这些副作用的机制尚未完全了解，也没有有效的治疗方法。在这里，我们发现，腹腔注射OXA引起的短期记忆障碍和焦虑样和抑郁样行为，（4 mg/kg/天，连续5天）伴随着突触功能障碍和海马中N-甲基-D天冬氨酸受体的NR 2B亚单位的下调，长期口服L-苏糖酸镁可预防OXA诱导的行为和突触变化（L-TAMS，604 mg/kg/天，结果表明，OXA注射液能显著降低血清和脑脊液中游离Mg~（2+）的含量Mg~（2+）缺乏（0.8 ~ 0.6 mmol/L），（0.6 mmol/L）上调培养海马脑片中肿瘤坏死因子（TNF-α）和核因子-κ B（NF-κB B）的活性形式磷酸化p65（p-p65），下调NR 2 B亚基，口服L-TAMS可抑制OXA诱导的TNF-α和p-p65的上调，以及海马和内侧前额叶皮质中的小胶质细胞活化。最后，与口服L-TAMS类似，侧脑室注射NF-κB抑制剂PDTC也可预防OXA诱导的记忆/情绪缺陷以及TNF-α、p-p65和小胶质细胞的变化。综合来看，脑内Mg~（2+）减少引起的TNF-α/NF-κB信号通路激活是OXA所致记忆/情绪障碍的重要原因，长期口服L-TAMS可能是治疗化疗所致记忆/情绪障碍的一种新途径。
Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxietylike and depression-like behaviors induced by intraperitoneal injections of OXA(4 mg/kg per day for 5 consecutive days)were accompanied by synaptic dysfunction and downregulation of the NR2B subunit of N-methyl-Daspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg~(2+) in serum and cerebrospinal fluid(from *0.8 mmol/L to *0.6 mmol/L).The Mg~(2+) deficiency(0.6 mmol/L)upregulated tumor necrosis factor(TNF-α)and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-κB),and downregulated the NR2B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-κB inhibitor,also prevented the OXAinduced memory/emotional deficits and the changes in TNF-α,p-p65,and microglia.Taken together,the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg~(2+) is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.
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影响因子：
34.7
作者：
Lee, Yong-Seok;Silva, Alcino J.
通讯作者：
Silva, Alcino J.
影响因子：
3.2
作者：
Chun-Yuh Yang;H. Chiu;S. Tsai;Trong-Neng Wu;Chin-Ching Chang
通讯作者：
Chun-Yuh Yang;H. Chiu;S. Tsai;Trong-Neng Wu;Chin-Ching Chang
DOI：
--
发表时间：
2001-07
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
J. Ballenger;Jonathan R. T. Davidson;Y. Lecrubier;D. Nutt;Richard D Jones;R. Berard
通讯作者：
J. Ballenger;Jonathan R. T. Davidson;Y. Lecrubier;D. Nutt;Richard D Jones;R. Berard
影响因子：
3.5
作者：
M. Fakih
通讯作者：
M. Fakih
影响因子：
15.1
作者：
Fourrier, Celia;Bosch-Bouju, Clementine;Castanon, Nathalie
通讯作者：
Castanon, Nathalie