Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-α/NF-κB Signaling in Rats
Xin Zhou1 • Zhuo Huang1 • Jun Zhang1 • Jia-Liang Chen3 • Pei-Wen Yao1 • Chun-Lin Mai1 • Jie-Zhen Mai1 • Hui Zhang2 • Xian-Guo Liu1,4
1 Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
2 Department of Anesthesiology, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
3 Department of Urology, Third Affiliated Hospital of Sun Yatsen University, Guangzhou 510630, China
4 Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
Abstract
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.
Keywords
Magnesium-L-threonate; Oxaliplatin; Tumor necrosis factor-alpha; Nuclear factor-kappaB; Cognitive deficit; Hippocampus; Medial prefrontal cortex
