Oxidative Stress and the CNS

Re: Bernhard

Bernhard H.J. Juurlink
juurlink@duke.usask.ca

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.
��BJ

Sun Dec 13