MRI spectroscopic and tractography studies indicate consequences of long-term ketogenic diet

Abstract

To maintain its functional abilities, the mature brain obtains energy from glucose produced in carbohydrate metabolism. When carbohydrates are eliminated from the diet, the energy comes from the oxidation of fatty acids. In this metabolic state called ketosis, ketone bodies are formed: β-hydroxybutyric acid (bHb), acetone, and acetoacetate as alternative source of energy passing through the blood-brain barrier easily. The ketosis state can be achieved through various strategies like caloric restriction, supplementation with medium-chain triglycerides, intense physical training, or ketogenic diet (KD). Using KD, drug-resistant epilepsy has been successfully treated in children and adults. It can also exert neuroprotective influences in cases of brain damage, glioblastoma multiforme, and Alzheimer's or Parkinson's diseases. Although many possible mechanisms of KD activity have been proposed, newer hypotheses appear with the research progress, mostly characterizing the brain under pathological but not normal conditions. Since different pathological conditions may affect the mechanism of KD action differently, additional research on the normal brain appears reasonable. For this purpose, young adult rats were treated with 4-month-lasting KD. Then, MRI structural measurements, spectroscopy, and tractography were performed. The procedures revealed significant increases in the concentration of glutamine, glutamate, glutathione and NAA, accompanied by changes in the pattern of neuronal connections of the striatum and hippocampal formation. This implies a possible involvement of these structures in the functional changes occurring in the brain after KD application. Thus, the investigations on the normal brain add important details concerning mechanisms underlying KD effects without their possible modification by a pathological status.

Ketogenic Diet Impairs Neurological Development of Neonatal Rats And Affects Biochemical Composition of Maternal Brains. Evidence of Functional Recovery In Pups

“…It may suggest a generalized nature of the previously described changes. In contrast, our studies on normal animals, that were fed KD for 4 months, showed increases in the number of myelinated bers passing through the hippocampal formation, striatum, internal capsule and pons (Gzieło et al, 2020). These differences might depend on the length of time during which the diet was applied.…”

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents

“…This may indicate that metabolic ketosis furnishes mitochondria with TCA cycle substrates ( 17 ). Furthermore, a 4-month KD elevated Glu and glutamine in young adult rats ( 36 ), and although human patients with epilepsy did not show differences in posterior cingulate cortical Glu measures compared to controls, elevated Glu concentrations predicted short-term freedom from seizures, hence indicating clinical relevance of elevated Glu in epilepsy ( 37 ). In the meantime, a recent study found that acetone and BHB acted as inhibitors of Glu at the excitatory NMDA ( N -methyl- d -aspartate) receptors ( 38 ).…”

“…Our preclinical finding that a history of KD decreased alcohol consumption, however, merits further investigation for we do not have clinical data on long-lasting effects of KD on alcohol abstinence. Although preclinical studies have not been reported on long-lasting effects of KD on brain glucose metabolism, there are reports of long-lasting changes in brain structure and neurochemistry following a KD, including elevated glutamate and glutamine ( 36 ). Thus, future studies are needed to assess whether there are long-lasting changes in brain glucose metabolism that persist after KD discontinuation.…”

Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder

“…A recent study in a mouse model of Alzheimer's Disease (triple transgenic Alzheimer's 3xTgAD, which shows reduced brain glucose utilization) showed higher hippocampal glutamate and α-ketoglutarate (a precursor of glutamate) in animals who received a KE diet compared to regular chow and a positive correlation between glutamate and α-ketoglutarate levels in both groups ( 50 ). Thus, nutritional ketosis appears to furnish mitochondria with TCA cycle substrates ( 38 ), as evidenced by the finding that a 4-month KD elevated glutamate and glutamine in young adult rats ( 81 ). Although patients with epilepsy did not show differences from controls in posterior cingulate cortical glutamate measures, patients' elevated glutamate concentrations predicted short-term freedom from seizures, supporting the clinical relevance of glutamate concentrations in epilepsy ( 82 ).…”