Kynurenic acid inhibits the release of the neurotrophic fibroblast growth factor (FGF)-1 and enhances proliferation of glia cells, in vitro.
1. Kynurenic (KYNA) and quinolinic (QUIN) acids are neuroactive tryptophan metabolites formed along the kynurenine pathway: the first is considered a non-competitive antagonist and the second an agonist of glutamate receptors of NMDA type. The affinity of these compounds for glutamate receptors is, however, relatively low and does not explain KYNA neuroprotective actions in models of post-ischemic brain damage. 2. We evaluated KYNA effects on the release of fibroblast growth factor (FGF)-1, a potent neurotrophic cytokine. Because KYNA exhibits a neuroprotective profile in vitro and in vivo, we anticipated that it could function as an autocrine/paracrine inducer of FGF-1 release. Studies were performed in several models of FGF-1 secretion (FGF-1 transfected NIH 3T3 cells exposed to heat shock, A375 melanoma cells exposed to serum starvation, growth factor deprived human endothelial cells). To our surprise, KYNA, at low concentration, inhibited FGF-1 release in all cellular models. QUIN, a compound having opposite effects on glutamate receptors, also reduced this release, but its potency was significantly lower than that of KYNA. 3. KYNA and QUIN also displayed a major stimulatory effect on the proliferation rate of mouse microglia and human glioblastoma cells, in vitro. 4. Our data suggest that minor changes of local KYNA concentration may modulate FGF-1 release, cell proliferation, and ultimately tissue damage in different pathological conditions.
Di Serio
Claudia
C
Department of Critical Care Medicine and Surgery, Geriatric Medicine Unit, University of Florence, School of Medicine, Viale Pieraccini n. 6, Florence, 50139, Italy.
Cozzi
Andrea
A
Angeli
Ilaria
I
Doria
Laura
L
Micucci
Isabella
I
Pellerito
Silvia
S
Mirone
Patrizia
P
Masotti
Giulio
G
Moroni
Flavio
F
Tarantini
Francesca
F
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D017378:Quinolinic Acid / Q000494:pharmacology
D017077:Culture Media, Conditioned; D018691:Excitatory Amino Acid Antagonists; D016220:Fibroblast Growth Factor 1; D017378:Quinolinic Acid; D007736:Kynurenic Acid