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

AbstractAntineoplastic 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 andp-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...
Source: Neuroscience Bulletin - Category: Neuroscience Source Type: research