Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

Abstract

Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.

Ketogenic effect of coconut oil in ALS patients

“…Based on this assumption, research on SOD1 G93A mice indicates that a KetoDi could slow the progression of ALS’s clinical and biological signs ( 17 ). A KetoDi enhances the production of KBs, compounds that neurons can utilize as an energy source in the brain ( 18 ). Since KBs can exert neuroprotective effects, it has been suggested that inducing moderate ketosis through regular consumption of medium-chain fatty acids could be beneficial ( 17 , 19 ).…”

“…Consequently, potential KetoDi-related biomarkers may include (but not limited to): (a) elevated levels of BHB and acetoacetate (AA) in blood and cerebrospinal fluid (CSF), which indicate ketosis; (b) improved ATP production, a marker of enhanced mitochondrial function; (c) increased cytochrome c oxidase activity, which indicates better mitochondrial respiratory chain function; (d) reduced levels of isoprostanes, protein carbonyls and/or 8-hydroxy-2′-deoxyguanosine, which reflect oxidation of lipids, proteins and DNA, respectively; (e) elevated superoxide dismutase activity, which indicates improved antioxidant defense; (f) lower levels of C reactive protein and pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6); (g) elevated BDNG, which associates with neuroprotection and neuronal health ( 18 , 29 , 30 ).…”