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Exposure to hypobaric hypoxia(HH)cause multiple aspects of neuron cell damage,and consequently result in the impaired cognitive function.Studies on experimental models have revealed that there are several mechanisms underlying these cognitive deficits,like oxidative stress,Glutamate mediated excitotoxicity,altered ion channels et al.Accordingly,application of modulators of these pathways is beneficial to ameliorate the memory dysfunction.Since HH exposure produce much a complex and comprehensive stress on the brain,targeting the single modifier usually display inadequate neuro-protection,and the efficacy is limited.Therefore,a drug,which antagonizes the HH stress at a broader dimension and at multi-levels,is a promising strategy to improve HH-induced memory impairment.ketogenic diet(KD)have been successfully used to treat drug-resistant epilepsy.Experimental and clinical data demonstrated that it can enhance cognitive function in both pathophysiological and normal healthy experimental animal systems.However,the underlying mainstreams remains to be illustrated.In the present study,we attempt to study the possible protective effect of KD against acute HH-induced cognition deficits and to investigate the possible mechanisms in adult rats.Eight-weeks old male SD rats were fed with normal diet or classical KD recipe for 2 weeks and then be subjected for Morris water maze test.The results showed that rats in KD group show a significant enhancement in learning and memory,as indicated by reduced escape latency during the consecutive five days of the acquisition trial and increased crossing number,more time in the target quadrant during probe trial.More interestingly,this observed change was not based on altered anxiety or locomotor activity.The corresponding biochemical analysis showed that KD treatment significantly elevated serum levels of betahydroxybutyrate and acetoacetate,two ketone bodies produced by fatty acid metabolism.Since beta-hydroxybutyrate is an endogenous and specific inhibitor of histone deacetylase,the acetylation levels of histone H3 and histone h4 in hippocampus were detected.Western and immunohistochemistry results all showed that KD treatment increased acetylated levels of histone H3(Lys 9,Lys14)and histone H4(Lys12).Real time-PCR analysis found that accompanied with the increased histone acetylation modification,the mRNA levels of memory-related genes,like BDNF,EGR1,and FOS were increased in KD-treated rats.Exposure of rat to acute HH(simulated altitude of 7000 m,24 h)resulted in less cross number,longer latency to first pass through platform,less time in the target quadrant during probe trial,However,these parameters are all reversed by KD pre-treatment,suggesting that KD treatment improve acute HH-induced spatial memory deficits.Furthermore,KD treatment also reversed acute HH-induced decreased levels of histone acetylation of histone H3 and histone H4.Taken together,KD treatment not only enhance learning and memory in adult rats,but also significantly improve acute HH-induced spatial memory deficits mainly through increased acetylation modification of histone H3 and histone H4 and enhanced gene expression.Therefore,the potential preventive role of KD in mountain sickness may be utilized in the near future and deserves further exploration.