Oxidation of Serotonin by Superoxide Radical:  Implications to Neurodegenerative Brain Disorders

Abstract

Many new lines of evidence implicate both superoxide anion radical (O2*-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate-mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5-hydroxytryptamine (5-HT, serotonin) by an O2*--generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2*--mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4, 5-D). However, O2*- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4, 4'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)-5-hydroxy-1H-indol-4-yl]-2,6,8-triketo-1H,3H, 7H-purine (7) as the major products. These products differ from those formed in the HO*-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)tryptamine-4,5-dione, whereas the putative carbocation intermediate is scavenged to give 4-(S-glutathionyl)-5-hydroxytryptamine. T-4,5-D also reacts with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and inhibits its activity. Previous investigators have proposed that T-4, 5-D is a serotonergic neurotoxin. This raises the possibility that T-4,5-D and perhaps other putative intraneuronal metabolites formed by the O2*-/H2O2/oxo-iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.

Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation

“…Normally, excess 5-HT is enzymatically converted to compounds such as 5-HIAA, one of several stable oxidized forms of indoleamine. Under conditions of oxidative stress, polymerized products of indoleamine oxidation can form and have been implicated in the etiology of neurodegenerative diseases such as AD, several psychotic diseases, and the neurodegenerative effects of amphetamines (37). The primary aberrant oxidation products of 5-HT, such as tryptamine diones, undergo rapid dimerization resulting in fluorescent compounds colocalized with the monoamine pool.…”

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

“…More recently, Dryhurst and coworkers (Jiang et al 1999;Wrona and Dryhurst 1998) have identified a number of toxic 5-HT metabolites, in addition to 5,6-DHT, but the in vivo synthesis of these metabolites has not been demonstrated. Because no studies have assessed the formation of toxic 5-HT metabolites after injection of FEN or dFEN, this issue remains unresolved.…”

Superoxide Anion-Scavenging Effect of 2-Amino-1,3-selenazoles

“…Excesses of superoxide anion in the human body are kept in check by an antioxidant enzyme system including SOD, GPX, and catalase (Cat). Superoxide anion has been reported to cause nerve degeneration 12) and heart failure. 13) SOD activity in blood sample from patients with thyroiditis, dwarfism, and Turner syndrome has been found to be lower than in healthy persons.…”