Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-a/NF-j B Signaling in Rats

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 NR2 B 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 NR2 B 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.