Oxidative Stress and the CNS

Re: Bernhard

Bernhard H.J. Juurlink

Dear Marylin,  The mitochondrion is the major source of superoxide production under normal physiological conditions in most cells.  There are oxireductases in peroxisomes that produce superoxide/hydrogen peroxide, and this organelle may be a significant source.  Other sources are catecholamine oxidation (both enzymatic and non-enzymatic), arachidonate metabolism, respiratory burst enzymes in leukocytes, etc.  Superoxide production by mitochondria increases when the respiratory chain is fully charged by electrons - this would be when there is an ample supply of ATP and reducing equivalents such as NADH and FADH.  Under these conditions there is an increased chance of leakage of electrons from the carriers of the electron transport chain onto molecular oxygen.  I imagine that this is possibly the case with hyperglycemia.  It is also the case with hypoxia - this may seem somewhat counterintuitive but under hypoxia with oxygen tension down the electron carriers would tend to be fully reduced.  Another problem with hyperglycemia is that there is an increase in glycation endproducts.  Such endproducts can interact with the receptor of advanced glycation endproducts (RAGE) to increase oxidative stress.  Both oxidative stress and glycation endproducts (perhaps through increasing oxidative stress) increase the chances of activation of NFkappB and hence increase the expression of pro-inflammatory genes such as cycloxygenase-2 (its enzymatic actions also produces superoxide), proinflammatory cytokines, etc.

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