Characterization of 2,4,5-trihydroxyphenylalanine neurotoxicity in vitro and protective effects of ganglioside GM1: implications for Parkinson's disease.
The neurotoxic properties of 2,4,5-trihydroxyphenylalanine (TOPA; the 6-hydroxylated derivative of dopa) was investigated in cultures of central neurons. Application of solutions of TOPA to cerebellar granule cells resulted in a concentration- and time-dependent neuronal death, with prolonged (24 hr) exposure producing a clear left-handed shift in the dose-response relationship from the one observed with a 60-min exposure (LD50: 4 and 29 microM, respectively). This toxicity was largely blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Solutions of TOPA were also toxic to mesencephalic neurons after acute or chronic exposure, displaying the same leftward shift in LD50. This latter preparation contained a minor population of dopaminergic, tyrosine hydroxylase immunopositive cells which were likewise sensitive to the excitotoxic effects of TOPA. Neurotoxic activity of TOPA appeared to depend upon its oxidation in solution, as judged using chemical analysis and reducing agents. The monosialoganglioside GM1 was effective in protecting against neurodegeneration induced by brief or prolonged exposure to solutions of TOPA. These results suggest that an abnormal production or accumulation of TOPA or its oxidation product(s) might be involved in excitotoxicity directed to areas of the brain with dopaminergic innervation, and in other brain areas in Parkinson's disease patients on long-term dopa therapy. The selective action of gangliosides in disrupting the pathological consequences of glutamate receptor activation proposes their use as chemoprophylactic agents for preventing or arresting the neuronal losses accompanying such situations.
Skaper
S D
SD
Fidia Research Laboratories, Abano Terme, Italy.
Facci
L
L
Schiavo
N
N
Vantini
G
G
Moroni
F
F
Dal Toso
R
R
Leon
A
A
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D005677:G(M1) Ganglioside / Q000494:pharmacology* / Q000627:therapeutic use; D020267:MPTP Poisoning; D008636:Mesencephalon / Q000187:drug effects*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000188:drug therapy*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D011810:Quinoxalines; C001388:6-hydroxydopa; D005677:G(M1) Ganglioside; D004295:Dihydroxyphenylalanine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione