The Brain Hypometabolism Hypothesis Part 123: An Overview

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There are a lot of posts on the Brain Hypometabolism Hypothesis (BHH) so I thought it would be useful to summarise them here and this can be cross-referenced with this post.

So to begin with there is a discussion about the nature of metabolism which leads onto the specification that the BHH refers to energy hypometabolism.

Energy Hypometabolism

There are several key processes

1. Glycolysis in which Glucose is converted into Pyruvate with the generation of ATP and generation of Acetyl CoA.
2. Generation of Acetyl CoA via Beta Oxidation of Fatty Acids
3. Generation of Acetyl CoA from Amino Acids via multiple pathways
4. The Citric Acid Cycle which utilises Acetyl CoA and which generates ATP and NADH.
5. Oxidative phosphorylation in which ATP is generated using an electron/proton gradient across the mitochondrial membrane.

Pathology

The discussion to date has considered two pathologies:-
1. Impaired glucose metabolism
2. Hypoxic Ischaemic Brain Injury

Impaired Glucose Metabolism

The metabolism of glucose in the brain is an area where there are large gaps in knowledge. There are specialised glucose receptors in the brain – referred to as the GLUT’s. There are at least 14 of these and two of them in particular GLUT 6 and GLUT 11 are poorly characterised. Some of the GLUT receptors are involved with other molecules (e.g. uric acid). However there is also evidence for a role for Insulin in the brain.

Looking at the empirical evidence there are large studies identifying an association between Diabetes and different forms of Dementia. The relevant question in this context is what is the mechanism(s) for this relationship.

Hypoxic Ischaemic Brain Injury

In Sekhon, Ainslie and Griesdale’s model brain injury results from a combination of primary cerebral hypoxia and cerebral perfusion induced secondary mechanisms. These can again be further expanded:-

Primary brain injury after hypoxia: A reduction in cerebral oxygen leads to a decrease in ATP production and a chain of events leading to the influx of Calcium ions into cells. A process referred to as NMDA mediated excitoxicity is thought to play role in this and was first identified in the early 70’s by Professor John Olney when investigating the effects of Glutamate analogues. Lai, Zhang and Wang relate this to a number of diseases such as Huntington’s Disease and Alzheimer’s Disease. They note that there are most likely different subpopulations of NMDA receptors that mediate long term potentiation (important for memory formation) and excitoxicity. The authors also note the complex functions of the Mitochondria as well as the regulation of these functions.

Secondary brain injury after hypoxia: There are seven factors postulated to play a role in the secondary brain injury following hypoxia – microvascular dysfunction, cerebral oedema, anaemia, impaired cerebral autoregulation, carbon dioxide, hyperoxia, hyperthermia.

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Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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