HIGH FAT DIET MODULATES NEUROPATHOLOGICAL, METABOLIC, AND CARDIOVASCULAR ALTERATIONS IN AN EXPERIMENTAL MODEL OF TRAUMATIC BRAIN INJURY

Abstract

Traumatic brain injury (TBI) constitutes a major public health concern in different countries and is one of the major causes of death globally. It has been established that even though TBI occurs in the brain, it can exert several systemic effects which can worsen the complications observed in TBI patients. Despite huge research output on TBI over the last few years, no therapy has been effectively approved by the FDA for its treatment. Hence, there has been an increasing need to understand factors that affect TBI outcome, to better understand its pathophysiology. One of such factors is diet and lifestyle. Western diet (WD), which is a high-fat diet (HFD) rich in saturated fat and refined sugar, has been reported to be associated with adverse effects on brain health. Some of the alterations that HFD triggers in the brain are similar to the manifestations of some neurological disorders. Beyond its direct impact on the brain, WD is linked to metabolic syndrome which is a significant risk factor for cognitive impairment and chronic diseases. Despite ample evidence on the systemic and neuronal effects of WD, only little is known about how it affects the outcome of TBI and how it contributes to secondary injury that follows the initial impact. In this study, we hypothesized that chronic exposure to HFD prior to TBI worsens the neural, behavioral, and cardiovascular outcomes observed in TBI alone, via aggravation of neuroinflammation, oxidative stress, cell proliferation disruption, neurodegeneration, and autophagic imbalance. C57BL6 mice were allocated to four groups: normal chow sham, normal chow TBI, HFD sham, HFD TBI. Mice were placed on HFD for four weeks, before being subjected to an open head, controlled cortical impact, after which they were resumed on the HFD for additional four weeks before sacrifice. The control group was sham-operated. Behavioral and neurological outcomes were assessed using novel object recognition, Morris water maze, and pole climbing. Echocardiography and blood pressure monitoring were performed to assess cardiovascular parameters, while nuclear magnetic resonance (NMR) was used to measure body composition. After sacrifice, the brain was extracted for molecular and histological analysis. Immunofluorescence was done to detect Gfap, Iba-1, NFL, pTau, and BrdU, which are markers of neuroinflammation, neurodegeneration, and cell proliferation. Western blot was done to detect Oxphos, LC3, Beclin, SOD, mTOR, and ATG 14, while RT-PCR was used to investigate oxidative stress markers (SOD, Catalase, and Nrf2). Two months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD led to an increased blood glucose, percentage fat, and body weight. Spatial learning and memory, as well as motor coordination, were significantly impaired by HFD and TBI. Immunofluorescence showed that HFD feeding pre- and post-TBI aggravated neuroinflammation, which was demonstrated by increased reactivity of microglia and astrocytes, neuro and axonal degeneration showed by diminished NFL staining and pTau accumulation, and repressed cell proliferation which was demonstrated through BrdU assay. Furthermore, HFD was associated with increased cortical and hippocampal ROS after TBI, which was followed by the repression of the antioxidant defense system. There was no difference in the oxphos complexes and autophagy markers. HFD led to an adverse remodeling of the left ventricular function, by causing a reduction in ejection fraction and fractional shortening, as well as leading to a slightly increased blood pressure. Indeed, HFD was associated with adverse neuropathologic effects following TBI. Specifically, we demonstrated that HFD is associated with aggravated neurological deficits, neuroinflammation, oxidative stress, and repressed cell proliferation. This demonstrates the extent to which diet-induced metabolic stress can worsen the outcome of TBI victims.