Does the O'Brien cycle occur in vivo as a key component in H(2)O(2) production and redox signalling?
This paper examines three hypotheses constructed to explain the cause of the desferrioxamine/prochlorperazine coma. This deep and prolonged (2-3days) coma results when normal doses of two widely used therapeutic agents (the iron chelator desferrioxamine and the dopamine receptor blocker prochlorperazine) are administered together in normal doses in humans and rats. The coma is more severe in iron-deficient rats suggesting that removal of iron and resulting neuronal iron deficiency by desferrioxamine is a contributory cause. Iron and dopamine are linked in the O'Brien cycle in which redox cycling occurs between ferric and ferrous iron linked to cycling between a catecholamine and its o-quinone. This cycle is a powerful transmuter of superoxide, that converts five molecules of superoxide into two molecules of water and three molecules of hydrogen peroxide. Hydrogen peroxide is a vital ingredient in many redox signalling mechanisms in neurons. Dopamine D2 receptor antagonists also inhibit the activation of hydrogen peroxide-producing superoxide dismutase in the postsynaptic neuron. The coma might be therefore due to collapse of the O'Brien cycle and lack of SOD resulting in a fall in hydrogen peroxide levels. Three different microanatomical loci are evaluated to explain how the coma might result from these redox reactions.
Center for Brain and Cognition, UCSD, 9500 Gilman Drive, La Jolla, CA 92093-0109, USA. smythies@psy.ucsd.edu
John
J
Smythies
D000818:Animals; D001921:Brain / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism*; D007501:Iron / Q000737:chemistry; D008954:Models, Biological; D008962:Models, Theoretical; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology; D010084:Oxidation-Reduction; D051381:Rats; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
D002395:Catecholamines; D018492:Dopamine Antagonists; D013481:Superoxides; D006861:Hydrogen Peroxide; D007501:Iron; D004298:Dopamine