IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric acid toxicity instriatal cultures

Glutaric acid (GA) and 3-hydroxyglutaric acid (3GA) are thought to contribu te to the degeneration of the caudate and putamen that is seen in some chil dren with glutaric acidaemia type I, a metabolic disorder caused by a gluta ryl-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 man ner; however, GA and 3GA were both more toxic than QUIN. The neurotoxic eff ects of low concentrations of GA or 3GA were additive to QUIN toxicity. A s eries of hormones and growth factors were tested for protection against GA and 3GA toxicity. Insulin (5-500 muU/ml), basic fibroblast growth factor (b FGF; 10 ng/ml), insulin-like growth factor (IGF-1; 50 ng/ml), brain-derived neurotrophic factor (BDNF; 10 ng/ml), glial-derived neurotrophic factor (G DNF; 10 ng/ml), and two glutamate antagonists were evaluated in brain cultu res 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 muU/ml) and IGF-1. BDNF and GDNF had no effects on neuronal surv ival. Glutamate antagonists MK801 (10 mu mol/L) and NBQX (10 mu mol/L) fail ed to prevent GA or 3GA neurotoxicity. We conclude that GA and 3GA are neur otoxic in cultures of embryonic rat striatum and cortex. Striatal neurons w ere rescued from death by bFGF and IGF-1 but not by glutamate antagonist, s uggesting that toxicity in this embryonic system is not necessarily mediate d by glutamate receptors.