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 anxiety-like 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-D-aspartate 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 Mg²⁺ in serum and cerebrospinal fluid (from ~ 0.8 mmol/L to ~ 0.6 mmol/L). The Mg²⁺ 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 OXA-induced 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 Mg²⁺ 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.

奥沙利铂 (OXA) 等抗肿瘤药物通常会导致记忆力和情绪障碍。目前，这些副作用背后的机制尚不完全清楚，也没有有效的治疗方法。在这里，我们表明腹膜内注射 OXA（每天 4 mg/kg，连续 5 天）引起的短期记忆缺陷和焦虑样和抑郁样行为伴随着突触功能障碍和 NR2B 亚基的下调。海马体中的 N-甲基-D-天冬氨酸受体，与记忆和情绪密切相关。长期口服镁-L可防止 OXA 诱导的行为和突触变化-苏糖酸盐（L-TAMS，每天 604 mg/kg，从前 2 天到实验结束）。我们发现 OXA 注射显着降低了血清和脑脊液中的游离 Mg ^{2+ （从 ~ 0.8 mmol/L 到 ~ 0.6 mmol/L）。}Mg ²⁺缺乏 (0.6 mmol/L) 上调肿瘤坏死因子 (TNF-α) 和磷酸化 p65 ( p -p65)，一种活性形式的核因子-kappaB (NF-κB)，并下调 NR2B 亚基。培养的海马切片。口服 L-TAMS 可防止 OXA 诱导的 TNF-α 和p上调-p65，以及海马和内侧前额叶皮层中的小胶质细胞激活。最后，与口服 L-TAMS 相似，脑室内注射 PDTC（一种 NF-κB 抑制剂）也可防止 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。总之，由脑 Mg ²⁺减少导致的 TNF-α/NF-κB 信号传导的激活是 OXA 诱导的记忆/情绪缺陷的原因。慢性口服 L-TAMS 可能是一种治疗化疗引起的记忆/情绪缺陷的新方法。