Therapeutic strategies for ketosis induction and their potential efficacy for the treatment of acute brain injury and neurodegenerative diseases

The therapeutic use of ketone bodies (KB) against acute brain injury and neurodegenerative disorders has lately been suggested by many studies. Several mechanisms responsible for the protective action of KB have been described, including metabolic, anti-inflammatory and epigenetic. However, it is still not clear whether a specific mechanism of action can be associated with a particular neurological disorder. Different strategies to induce ketosis including the ketogenic diet (KD), caloric restriction (CR), intermittent fasting (IF), as well as the administration of medium chain triglycerides (MCTs), exogenous ketones or KB derivatives, have been used in animal models of brain injury and in humans. They have shown different degrees of success to prevent neuronal damage, motor alterations and cognitive decline. However, more investigation is needed in order to establish safe protocols for clinical application. Throughout the present review, we describe the different approaches that have been used to elevate blood KB and discuss their effectiveness considering their advantages and limitations, as tested in models of brain injury, neurodegeneration and clinical research. We also describe the mechanisms of action of KB in non-pathologic conditions and in association with their protective effect against neuronal damage in acute neurological disorders and neurodegenerative diseases.