Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats

Abstract

Exposure to hypobaric hypoxia causes neuron cell damage, resulting in impaired cognitive function. Effective interventions to antagonize hypobaric hypoxia-induced memory impairment are in urgent need. Ketogenic diet (KD) has been successfully used to treat drug-resistant epilepsy and improves cognitive behaviors in epilepsy patients and other pathophysiological animal models. In the present study, we aimed to explore the potential beneficial effects of a KD on memory impairment caused by hypobaric hypoxia and the underlying possible mechanisms. We showed that the KD recipe used was ketogenic and increased plasma levels of ketone bodies, especially β-hydroxybutyrate. The results of the behavior tests showed that the KD did not affect general locomotor activity but obviously promoted spatial learning. Moreover, the KD significantly improved the spatial memory impairment caused by hypobaric hypoxia (simulated altitude of 6000 m, 24 h). In addition, the improving-effect of KD was mimicked by intraperitoneal injection of BHB. The western blot and immunohistochemistry results showed that KD treatment not only increased the acetylated levels of histone H3 and histone H4 compared to that of the control group but also antagonized the decrease in the acetylated histone H3 and H4 when exposed to hypobaric hypoxia. Furthermore, KD-hypoxia treatment also promoted PKA/CREB activation and BDNF protein expression compared to the effects of hypoxia alone. These results demonstrated that KD is a promising strategy to improve spatial memory impairment caused by hypobaric hypoxia, in which increased modification of histone acetylation plays an important role.

Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity

“…Gut commensals produce different short chain fatty acids as byproducts, among which BHB is one of the important [27] considering a few interesting related findings, such as exerting various neurological effects through the upregulation of BDNF and enhancing neuroprotection [46]. In addition, BHB is also known to cause acetylation of histone H3 [47], which implies the inhibition of histone deacetylase, which is again known to upregulate BDNF and GDNF and protect dopaminergic neurons [30]. On examining the brain tissues, we found elevated levels of BHB and histone H3 following probiotic administration.…”

Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections

“…In a variety of models of hypoxic and ischemic cerebral injury, treatment with exogenous BHB maintained brain ATP levels, increased neuron survival, decreased cerebral infarct volume, decreased cerebral edema, and improved cognitive performance. [172][173][174] Additionally, exogenous ketones mitigate inflammation and neuropathology in various model systems via adenosine 1a receptor activation, [175][176][177] suggesting ketones may attenuate HIF-1a-induced inflammation and oxidative stress in hypoxia. Furthermore, exogenous sources of ketones protect cognitive function during hypoglycemia in mice (A.P.K., unpublished data) and humans, 178 hypoxia in mice177 and humans (B.J.S.…”

The Future of Shift Work: Circadian Biology Meets Personalised Medicine and Behavioural Science

“…In preclinical studies, ketone bodies themselves have been found to have pleiotropic beneficial physiological effects, including modulation of inflammation, tissue-specific suppression of mTOR signalling, and increased production of brain-derived neurotrophic factor ( 89 – 91 ). If translatable to humans, these systemic effects of ketone bodies imply that long-term consumption of a KD could reduce risk of certain cancers and neurodegenerative diseases such as Alzheimer's in shift workers, particularly those that are already at increased risk ( 92 , 93 ).…”