Thiokynurenates prevent excitotoxic neuronal death in vitro and in vivo by acting as glycine antagonists and as inhibitors of lipid peroxidation.
Several derivatives of kynurenic and thiokynurenic acids were synthesized and tested for their ability to protect primary cultures of cerebellar granule cells against excitotoxic damage, and to affect the binding of [3H]glycine ([3H]Gly), [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA), [3H]3-(2-carboxypiperazine-4-yl-)propyl-1-phosphonic acid ([3H]CPP), [3H]kainic acid and [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) to rat cortical membranes. Kynurenic and thiokynurenic acid derivatives with one or two halogens in position 5 or 7 were selective glycine antagonists, failing to affect N-methyl-D-aspartate (NMDA), kainate or AMPA sites at micromolar concentrations. 7-Cl-kynurenic, 7-Cl-thiokynurenic, 5,7-diCl-kynurenic and 5,7-diCl-thiokynurenic acids had similar IC50s for displacing [3H]Gly from its strychnine-insensitive site and for reducing the stimulated (0.5 microM NMDA and 1 microM glycine) [3H]TCP binding to cortical membranes. However, 7-Cl-thiokynurenic acid was particularly potent to prevent excitotoxic neuronal death in cultured cerebellar granule cells. This action may be ascribed to inhibition of lipid peroxidation, a property which was demonstrated for the 5- or 7-Cl derivatives of thiokynurenic acid. Furthermore, 7-Cl-thiokynurenic acid reduced excitotoxic damage caused by the injection of quinolinic acid in the rat striatum. Thus, 7-Cl-thiokynurenic acid appears to be a new compound with interesting antiexcitotoxic properties both in vitro and in vivo.
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
F
F
Moroni
M
M
Alesiani
L
L
Facci
E
E
Fadda
S D
SD
Skaper
A
A
Galli
G
G
Lombardi
F
F
Mori
M
M
Ciuffi
B
B
Natalini
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D005998:Glycine / Q000037:antagonists & inhibitors*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; C076191:thiokynurenate; D018698:Glutamic Acid; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D005998:Glycine