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

Abstract

X. (2015). Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 59 68-75. Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory AbstractHigh fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic 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, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF 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 (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF dietinduced 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 hippocampus 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 < 0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus. AbstractHigh-fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic 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, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), HF (40% of energy as fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p<0.05). BM a...

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

“…Overall, Young HFHCtreated rats committed a larger number of WMC errors compared to the control rats, thereby revealing a diet effect. These data are in line with previous investigations in adult or juvenile rodents, showing a significant reduction in hippocampus-dependent behaviors following prolonged treatment with a HFHC diet [12,58,59], as well as in frontal cortex-related working memory [60]. Our findings demonstrate exacerbated cognitive impairment in aged rodents with this type of diet, and indicate that the aging process gives rise to a higher vulnerability to diet-induced alterations in hippocampal function.…”

Effects of high-fat diet exposure on learning & memory

“…In three reports that did find evidence of HF diet-related impairment, deficits were seen after 1 and 3 weeks on a 60% HF diet [67] as well as after 2, 3, and 4 months on a different 60% HF diet [24]. The most recent report found impairment after 21 weeks on 40% HF diet [85]. Another study using a 60% HF diet in male C57BL/6 mice did not find a diet effect on Novel Object Recognition, but did find impairment in the more hippocampal dependent object-in place variation of the test [86].…”

“…In fact, chronic inflammation in adipose tissue is thought to heavily contribute to the effects of HF diet and obesity on insulin sensitivity [115,116] which, as discussed above, may additionally impact learning and memory. Among the studies that have been reviewed here, several have found a HF diet-related increase in oxidative stress in the hippocampus [15–17,22,26,53,69,83] and cortex [17] as well as increased inflammatory cytokines in the hippocampus [17,55,85] and cortex [17,75, 85]. However, at least two reports have found no change in cytokines despite finding HF diet-induced cognitive impairment [67,86].…”

“…Finally, multiple studies have found that HF diet intake is associated with decreased expression of BDNF in both the hippocampus [13,14,16, 26,85,89] and cortex [15,67,75,85,89] suggesting that the negative effects of HF diet consumption on learning and memory may also be mediated in part by alteration of BDNF-related synaptic plasticity. This is further supported by at least three studies that have found HF diet-related loss of dendritic spines [14,56,76], though one study did find increased spine density in the hippocampus which the authors suggested may have been a compensatory mechanism [87].…”

Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder

“…BDNF-TrkB binding contributes to the control of activity dependent synaptic regulation, long term potentiation, and neurogenesis, which are all critical for learning and memory formation [35]. Similar to the hippocampus, intact BDNF-TrkB expression in the prefrontal cortex (PFC) can regulate working memory, discrimination reversal learning as well as object recognition learning [36–40]. Furthermore, effects of high fat diet on disrupting both hippocampal and cortical bdnf and trkb expression has been reported in rodent models [38, 40–42].…”