High-fat diets in traumatic brain injury: A ketogenic diet resolves what the Western diet messes up neuroinflammation and beyond

Traumatic brain injury (TBI) is a debilitating neurological condition which presents a major health burden. Neuronal and metabolic consequences of the trauma, be it single or multiple, mild or severe, extend beyond the acute, initial insult to a chronic, secondary injury which determines functional outcomes. Secondary injury processes comprise distorted cellular energy homeostasis, oxidative stress, neuroinflammation, and consequently apoptotic or necrotic cell death. In fact, the modifying effects of dietary components on neurobehavioral processes indicate a mediating role for metabolism in secondary injury. Indeed, neuronal markers, like brain-derived neurotrophic factor (BDNF), present a link between energy homeostasis and neuroplasticity. High-fat diets (HFD) were shown to differentially impact secondary injury by inducing distinct metabolic states. Particularly, a Western diet (WD), composed of high fat and sugar, aggravates secondary TBI worsening anxiety, as well as motor and cognitive function. Conversely, a high-fat, low-sugar ketogenic diet (KD) resolves these manifestations and suppresses TBI-induced excitotoxicity and epilepsy. Underlying mechanisms for the characteristic HFD-induced alterations of TBI include modulation of mitochondrial function demonstrated as changes in mitochondrial permeability transition pore (mPTP) expression and activity as well as variations in bioenergetics. Exaggerated oxidative stress and neuroinflammation are thought to contribute to such observations in a vicious cycle. Additionally, long-term epigenetic changes are also involved. This chapter highlights molecular mechanisms associated with WD and KD feeding in different experimental models of TBI and provides insight into potential therapeutic targets for the management of TBI consequences.