2,4,5-trihydroxyphenylalanine in solution forms a non-N-methyl-D-aspartate glutamatergic agonist and neurotoxin.
We have investigated the pharmacologic and neurotoxic properties of 2,4,5-trihydroxyphenylalanine [topa; the 6-hydroxylated derivative of 3,4-dihydroxyphenylalanine (dopa)] in central neurons. Application of solutions of topa to the chicken eyecup preparation results in glutamatergic responses mediated predominantly by non-N-methyl-D-aspartate receptors. Pharmacological activity depends upon oxidation in solution to a new compound. This compound is tentatively identified as topa quinone. Solutions of topa are toxic to cortical neurons in culture, and this toxicity is blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These results suggest that production or accumulation of topa or its oxidation products might be involved in excitotoxicity, especially in dopaminergic neurons and their projection targets.
Department of Neurology, Children's Hospital, Boston, MA.
P A
PA
Rosenberg
R
R
Loring
Y
Y
Xie
V
V
Zaleskas
E
E
Aizenman
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology; D002645:Chickens; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000187:drug effects; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D009799:Ocular Physiological Phenomena; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats
D009498:Neurotoxins; D011810:Quinoxalines; C001388:6-hydroxydopa; D004295:Dihydroxyphenylalanine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione