Effect of Hyperbaric Oxygen Therapy on Brain Function and Cognition in D-galactose Induced Aging Rats with Obese-insulin Resistance

Abstract

Obesity is the most common health problem around the world. The major causative factor of obesity is high fat diet (HFD) consumption. Previous studies reported that HFD-induced obesity mediated several pathologies in brain, including insulin resistance, oxidative stress, microglia activation, imbalanced mitochondrial dynamics, autophagy impairment, apoptosis, synaptic dysplasticity, and increased amyloid deposition, resulting in cognitive decline. As a consequence of modern life style, the prevalence of obesity among elderly population is increasing the global concern. Previous studies demonstrated that aging caused brain pathology and cognitive decline. To induce aging, D-galactose (D-gal) administration has been proven to be the appropriate model and reported to cause neurodegeneration as similar to the naturally aging. D-galactose in rodents increased brain senescence markers, which lead to stimulate oxidative stress, microglia activation, apoptosis, synaptic dysplasticity, amyloid deposition and resulting in cognitive dysfunction. However, the effects of D-gal induced aging on brain pathologies and cognition in obese-insulin resistance have never been explored. Therefore, we hypothesized that D-gal induced aging accelerates and aggravates brain pathology and cognitive decline in obese-insulin resistant condition. In order to prevent neurodegeneration of obesity and aging, there are a lot of studies on antioxidant and drugs, however, the adverse effects were unavoidable. Therefore, hyperbaric oxygen therapy (HBOT) become the treatment of choice which has fewer side effects, a non-invasive and painless treatment. A previous study has reported that HBOT significantly reduced D-gal induced learning and impairments by increasing antioxidant enzymes and decreasing oxidative stress, inflammation and aging-related proteins. However, the effects of HBOT on brain function and cognitive function in D-gal induced aging with or without obese-insulin resistance have never been investigated. Therefore, we hypothesized that HBOT improves brain function and cognitive function in both D-gal induced aging with or without obese-insulin resistant condition. To test the first hypothesis, one hundred and twelve male Wistar rats were separated into two groups to be fed on a normal diet (ND) or a high fat diet (HFD) for 20-weeks. At the end of 12 weeks, ND and HFD-fed rats were divided to inject with a vehicle (0.9% NSS, s.c.) or D-gal (150 mg/kg/d, s.c.) for 4 and 8 weeks. The cognitive test and brain pathologies were determined at 4 and 8 weeks after D-gal administration. The results showed that 1) both D-gal induced aging and obese-insulin resistance equally increased peripheral insulin resistance, aging markers, microglia activation, insulin receptor dysfunction, synaptic dysplasticity in hippocampus, resulting in cognitive decline; 2) D-gal induced aging aggravated oxidative stress, autophagy impairment, apoptosis, mitochondrial dynamics imbalance, leading to amyloid deposition in hippocampus of obese-insulin resistant rats; and 3) 8-week D-gal administration in obese-insulin resistant rats had worsened hippocampal pathologies such as oxidative stress, apoptosis, brain derived neurotropic factor and beta-secretase, when compared with those of 4-week D-gal administration in obese-insulin resistant rats. To test the second hypothesis, eighty-four male Wistar rats were separated into 2 groups to receive either normal diet (ND) or high-fat diet (HFD) for 22 weeks. At week 13, both ND and HFD groups were given vehicle (0.9% NSS, s.c.) or D-gal (150 mg/kg/d, s.c.) for 10 weeks. After that, ND rats treated with vehicle were subjected to sham-treated group, which were placed in the hyperbaric chamber, but only atmospheric pressure was given for 14 days. HFD rats treated with vehicle were given hyperbaric oxygen therapy (HBOT), which were placed in the hyperbaric chamber with 100% O2 at 2 ATA for 14 days. D-gal treated rats in both dietary groups were assigned to sham-treated group or HBOT group. At the end of experiment, the cognitive test and brain pathologies were determined. The results demonstrated that HBOT attenuated cognitive decline in D-gal induced aging, obese-insulin resistance and combined model of D-gal induced aging and obese-insulin resistance by restoring insulin sensitivity, balancing autophagy, oxidative stress, microglia activation, apoptosis and synaptic dysplasticity in hippocampus. Therefore, this study informs that hyperbaric oxygen therapy may be used as an effective treatment to reduce the neurodegeneration of aging and obesity. All of our findings suggest that both D-gal induced aging and obese-insulin resistance caused brain pathologies and cognitive impairment. However, combined model of aging and obesity could not aggravate cognitive dysfunction. Interestingly, HBOT attenuated brain pathologies and restored the cognitive function of aging, obesity and combined model. Therefore, these results are useful in clinical setting to reduce the negative effects of aging and obesity on brain and help to recover brain functions.