Ketones Exhibit Neuroprotective Effects via Antioxidant Properties

Keto4Life

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May 24, 2021
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KETONES INHIBIT MITOCHONDRIAL PRODUCTION OF REACTIVE OXYGEN SPECIES PRODUCTION FOLLOWING GLUTAMATE EXCITOTOXICITY BY INCREASING NADH OXIDATION

The ketogenic diet is often said to be neuroprotective and is seen to be helpful in multiple neurological conditions with the mitigation of intractable epilepsy being the most notable. However, it is still not yet fully understood exactly how the ketogenic diet has this effect in the brain. Research has shown that ketones are a “cleaner” burning fuel (compared to glucose) producing less free radicals (or Reactive Oxygen Species) in the body. This study sought to examine the possibility that one of the reasons the ketogenic diet confers neuroprotection could be from the antioxidant capabilities of ketones during the production of energy in the brain.

Similar to the ketogenic diet, research of calorie restricted diets has shown a neuroprotective effect as well. “Calorie restriction can decrease the risk of neurodegenerative disease and protect the brain against acute insults such as stroke (Mattson et al, 2002).” A common feature of a calorie restricted diet and the ketogenic diet is the production of ketones in the body (beta-hydroxybutyrate and acetoacetate). The authors of this study noted previous research that revealed various neuroprotective and antioxidant effects in the brain and heart:
  • For example, BHB (beta-hydroxybutyrate) prevents the death of hippocampal neurons exposed to Aβ1–42, protects cultured mesencephalic dopaminergic neurons from the toxic effects of 1-methyl-4-phenylpyridinium (MPP+, an inhibitor of NADH dehydrogenase that increases oxygen radical formation) and reduces brain injury in rodents subjected to glycolysis inhibition and focal or generalized ischemia (Kashiwaya et al, 2000; Suzuki et al, 2001 & 2002).
  • Furthermore, ACA (acetoacetate) protects hippocampal neurons against glycolysis inhibition in vivo and in vitro (Massieu et al, 2003). In parallel, clinical data suggest that seizure control in epileptic patients treated with the ketogenic diet correlates with the serum concentration of ketones (Gilbert et al, 2000).
  • Studies in cardiac tissue have suggested that ketones might reduce oxidative stress (Veech et al, 2001), a pathogenic process implicated in many disorders ranging from atherosclerosis and traumatic injuries to diseases more specific to the nervous system (Droge, 2002; Keller et al, 2005).
In the present study, the researchers chose to use a glutamate excitotoxicity model using Wistar rat neurons and neocortical mitochondria exposed to high levels of calcium to assess the antioxidant effect of ketones under theses conditions. Glutamate is the most abundant amino acid in the brain and acts as the primary excitatory neurotransmitter in neuronal functioning. However, too much glutamate can create a pathological condition known as glutamate excitotoxicity which results in the death of neurons.

The authors concluded:
“In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress.”

In addition, the authors also mentioned that previous research has provided contradictory results regarding the antioxidant effects of beta-hydroxybutyrate and acetoacetate when observed individually using different models (i.e. brain vs heart tissue). The authors believe that the differences “most probably reflect technical and tissue-specific differences.” They further expound: “Nevertheless, our findings, made in neurons and isolated neuronal mitochondria without added respiratory inhibitors, indicate that a combination of ACA and BHB (which potentially better mirrors brain physiological conditions compared to previous studies employing one ketone body or the other) exert a neuroprotective, antioxidant effect by decreasing ROS production in neuronal tissues.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865572/