Inhibition of the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes by a putative aberrant metabolite of serotonin, tryptamine-4,5-dione.
A transient energy impairment with resultant release and subsequent reuptake of 5-hydroxytryptamine (5-HT) and NMDA receptor activation with consequent cytoplasmic superoxide (O(2)(-)(*)), nitric oxide (NO(*)), and peroxynitrite (ONOO(-)) generation have all been implicated in a neurotoxic cascade which ultimately leads to the degeneration of serotonergic neurons evoked by methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). Such observations raise the possibility that the O(2)(-)(*)/NO(*)/ONOO(-)-mediated oxidation of 5-HT, as it returns via the plasma membrane transporter to the cytoplasm of serotonergic neurons when the MA/MDMA-induced energy impairment begins to subside, may generate an endogenous neurotoxin. In vitro the O(2)(-)(*)/NO(*)/ONOO(-)-mediated oxidation of 5-HT forms tryptamine-4,5-dione (T-4,5-D). When incubated with intact rat brain mitochondria, T-4,5-D strongly inhibits state 3 respiration with pyruvate or alpha-ketoglutarate as substrates at concentrations which do not affect succinate-supported (complex II) respiration. Experiments with freeze-thawed rat brain mitochondria reveal that T-4,5-D inhibits the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. These and other properties of T-4,5-D raise the possibility that it may be an endogenously formed intraneuronal metabolite of 5-HT that contributes to the serotonergic neurotoxicity of MA and MDMA.
Jiang
Xiang-Rong
XR
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
Dryhurst
Glenn
G
D000818:Animals; D001921:Brain; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045563:Indolequinones; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000737:chemistry / Q000633:toxicity; D008928:Mitochondria; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000633:toxicity; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014363:Tryptamines / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D045563:Indolequinones; D011768:Pyruvate Dehydrogenase Complex; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D008694:Methamphetamine; D007655:Ketoglutarate Dehydrogenase Complex; D018817:N-Methyl-3,4-methylenedioxyamphetamine