IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric acid toxicity in striatal cultures.
Glutaric acid (GA) and 3-hydroxyglutaric acid (3GA) are thought to contribute to the degeneration of the caudate and putamen that is seen in some children with glutaric acidaemia type I, a metabolic disorder caused by a glutaryl-CoA dehydrogenase deficiency. This study assessed the neurotoxicity of GA and 3GA (0-50 mmol/L) compared to quinolinic acid (QUIN) in striatal and cortical cultures. All three acids were neurotoxic in a dose-dependent manner; however, GA and 3GA were both more toxic than QUIN. The neurotoxic effects of low concentrations of GA or 3GA were additive to QUIN toxicity. A series of hormones and growth factors were tested for protection against GA and 3GA toxicity. Insulin (5-500 microU /ml), basic fibroblast growth factor (bFGF; 10 ng/ml), insulin-like growth factor (IGF-1; 50 ng/ml), brain-derived neurotrophic factor (BDNF; 10 ng/ml), glial-derived neurotrophic factor (GDNF; 10 ng/ml), and two glutamate antagonists were evaluated in brain cultures to which 7 mmol/L GA or 3GA were added. GA and 3GA neurotoxicities were prevented by bFGF. Attenuation of 3GA-induced neurotoxicity was seen with insulin (5 microU/ml) and IGF-1. BDNF and GDNF had no effects on neuronal survival. Glutamate antagonists MK801 (10 micromol/L) and NBQX (10 micromol/L) failed to prevent GA or 3GA neurotoxicity. We conclude that GA and 3GA are neurotoxic in cultures of embryonic rat striatum and cortex. Striatal neurons were rescued from death by bFGF and IGF-1 but not by glutamate antagonist, suggesting that toxicity in this embryonic system is not necessarily mediated by glutamate receptors.
Bjugstad
K B
KB
Division of Clinical Pharmacology and Toxicology, University of Colorado Health Science Center, Denver, Colorado, USA.
Zawada
W M
WM
Goodman
S
S
Freed
C R
CR
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005977:Glutarates / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D006133:Growth Substances / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects*; D009410:Nerve Degeneration / Q000473:pathology; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014364:Tryptophan / Q000378:metabolism
C108959:3-hydroxyglutaric acid; D018691:Excitatory Amino Acid Antagonists; D005977:Glutarates; D006133:Growth Substances; D007328:Insulin; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D014364:Tryptophan; D017378:Quinolinic Acid; C035736:glutaric acid