5,5'-Dihydroxy-4,4'-bitryptamine: a potentially aberrant, neurotoxic metabolite of serotonin.
Previous investigators have detected unknown oxidized forms of 5-hydroxytryptamine (5-HT) in the CSF of Alzheimer's disease (AD) patients. Furthermore, an unidentified autoxidation product of this neurotransmitter is an inhibitor of acetylcholinesterase (AChE), an enzyme compromised in the Alzheimer brain. In this study it is demonstrated that the major product of autoxidation of 5-HT is 5,5'-dihydroxy-4,4'-bitryptamine (DHBT). Central administration of DHBT to mice at a dose of 40 micrograms (free base) evokes profound behavioral responses, which persist until the animals die (approximately 24 h). One hour after central administration of DHBT, the levels of norepinephrine, dopamine, 5-HT, and acetylcholine and their metabolites in whole brain are greatly elevated. Disturbances to the catecholaminergic and serotonergic systems were still evident shortly before the death of animals. DHBT is also shown to be a noncompetitive inhibitor of AChE in vitro. These observations suggest that if DHBT is formed as an aberrant metabolite of 5-HT in the human brain, it could potentially be neurotoxic and contribute to the neuronal degeneration and other neurochemical and neurobiochemical changes associated with AD or perhaps other neurodegenerative diseases.
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019.
M Z
MZ
Wrona
R N
RN
Goyal
D J
DJ
Turk
C L
CL
Blank
G
G
Dryhurst
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000096:biosynthesis*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010084:Oxidation-Reduction; D012701:Serotonin / Q000378:metabolism*; D014363:Tryptamines / Q000096:biosynthesis* / Q000494:pharmacology / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D018377:Neurotransmitter Agents; D014363:Tryptamines; C076856:5,5'-dihydroxy-4,4'-bitryptamine; D012701:Serotonin