Oxidative reactions and schizophrenia: a review-discussion.
Now that definitive direct evidence has been obtained that oxidized metabolites of catecholamines-aminochrome (derived from dopamine) and related compounds-occur in the human brain the question this paper explores is what is their function there, if any. They are precursors of neuromelanin and are formed inter alia by co-oxidation by prostaglandin H synthase during the synthesis of prostaglandin H from arachidonic acid. Their further metabolism by NAHPD-cytochrome P450 reductase forms the highly neurotoxic o-semiquinone together with free oxygen radicals. The defenses against these orthoquinones (o-quinones) and o-semiquinones (which include reduction, O-methylation, 5-cysteinylization, glutathione conjugation, conversion to the o-hydroquinone, and neuromelanin formation), and their possible status in schizophrenia, are reviewed. This system is closely linked with glutamate neurotoxicity because glutamate receptors activate PGH synthase and because dopamine toxicity is mediated by these o-quinones acting on NMDA receptors. Interactions between glutamate and dopamine neurotoxicity are explored, including a possible role for the redox properties of catecholamines. The hypothesis is presented that some of the demonstrated cellular damage in the schizophrenic brain may be mediated by catecholamine o-quinones. The significance of the evidence from previous studies carried out 40 years ago, that a closely related catecholamine o-quinone-adrenochrome-has psychotomimetic properties in humans and behavior disrupting properties in animals, is reviewed in the light of these recent findings.
Smythies
J R
JR
Department of Neuropsychiatry, Institute of Neurology, London, UK. smythies@psy.ucsd.edu
D001923:Brain Chemistry; D002395:Catecholamines / Q000378:metabolism*; D006801:Humans; D008543:Melanins / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000502:physiology*; D012559:Schizophrenia / Q000209:etiology / Q000503:physiopathology*
D002395:Catecholamines; D008543:Melanins; D017382:Reactive Oxygen Species; C014121:neuromelanin; D011451:Prostaglandin-Endoperoxide Synthases