Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

High fat (14F) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of olcanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, barcloxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HE diet. C57BL,6J male mice were fed a lab chow (LC) (5% of energy as fat), a HE (40% of energy as fat), or a HI' diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNE) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-n-aspartate (NMDA) receptor binding. BM treatment prevented HF diet induced impairment in recognition memory (p < 0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p < 0.05), however, no changes were seen in the hippocampus (p > 0.05). In the PFC and hippocarnpus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP activated protein kinase (pAMPK) (p < 005), BM adminislialion also prevented the I-IF dieL-induced increase in the protein levels of inflammatory molecules, phosphorylaLecl c-Jun N-Lerminal kinase (pJNK) in Lhe PIT, and prolein tyrosine phosphalase 1B (PTP1B) in both the PIT and hippocampus. In summary, Lhese findings suggest that BM prevents HF diet induced impairments in recognilion memory by improving downstream BDNIF signal transduction, increasing pAMPK, and reducing inflammanor' in Lhe PIT and hippocampus. (C) 2015 Elsevier Inc. All righLs reserved.