Age and Brain Structural Related Effects of Glutaric and 3-Hydroxyglutaric Acids on Glutamate Binding to Plasma Membranes During Rat Brain Development

Abstract

(1) In the present study we determined the effects of glutaric (GA, 0.01-1 mM) and 3-hydroxyglutaric (3-OHGA, 1.0-100 microM) acids, the major metabolites accumulating in glutaric acidemia type I (GA I), on Na(+)-independent and Na(+)-dependent [(3)H]glutamate binding to synaptic plasma membranes from cerebral cortex and striatum of rats aged 7, 15 and 60 days. (2) GA selectively inhibited Na(+)-independent [(3)H]glutamate binding (binding to receptors) in cerebral cortex and striatum of rats aged 7 and 15 days, but not aged 60 days. In contrast, GA did not alter Na(+)-dependent glutamate binding (binding to transporters) to synaptic membranes from brain structures of rats at all studied ages. Furthermore, experiments using the glutamatergic antagonist CNQX indicated that GA probably binds to non-NMDA receptors. In addition, GA markedly inhibited [(3)H]kainate binding to synaptic plasma membranes in cerebral cortex of 15-day-old rats, indicating that this effect was probably directed towards kainate receptors. On the other hand, experiments performed with 3-OHGA revealed that this organic acid did not change Na(+)-independent [(3)H]glutamate binding to synaptic membranes from cerebral cortex and striatum of rats from all ages, but inhibited Na(+)-dependent [(3)H]glutamate binding to membranes in striatum of 7-day-old rats, but not in striatum of 15- and 60-day-old rats and in cerebral cortex of rats from all studied ages. We also provided some evidence that 3-OHGA competes with the glutamate transporter inhibitor L-trans-pyrrolidine-2,4-dicarboxylate, suggesting a possible interaction of 3-OHGA with glutamate transporters on synaptic membranes. (3) These results indicate that glutamate binding to receptors and transporters can be inhibited by GA and 3-OHGA in cerebral cortex and striatum in a developmentally regulated manner. It is postulated that a disturbance of glutamatergic neurotransmission caused by the major metabolites accumulating in GA I at early development may possibly explain, at least in part, the window of vulnerability of striatum and cerebral cortex to injury in patients affected by this disorder.

Marked reduction of Na+, K+-ATPase and creatine kinase activities induced by acute lysine administration in glutaryl-CoA dehydrogenase deficient mice

“…Furthermore, excitotoxicity and epilepsy have been related to a diminution of Na + , K + -ATPase activity [54,55]. Our present data, allied to previous works showing that GA and 3HGA inhibit in vitro this enzyme in primary neuronal cultures from chick embryo telencephalon and in rat brain [14,27], as well as alter glutamate uptake and induces glutamate receptor activation [13,15,17,19,20,27,56], reinforce the hypothesis that excitotoxicity may represent an important mechanism of brain damage in GA I.…”

“…However, progressive neurological symptoms with mental developmental delay and hypotonia without apparent acute episodes may also occur in a considerable number of patients [5][6][7][8][9]. Neuroradiological imaging shows, besides basal ganglia degeneration, widened Sylvian fissures, cortical atrophy with frontotemporal volume loss, delayed myelination, ventriculomegaly and subdural hemorrhages [1,5,6,8,10,11] Although the pathogenesis of the brain damage in GA I is not fully established, accumulating evidence from in vitro and in vivo experiments performed in brain tissue and cultivated neural cells from rodents and chick suggest that excitotoxicity [6,[12][13][14][15][16][17][18][19][20][21], oxidative stress [22][23][24][25][26][27][28][29][30][31] and cellular bioenergetic dysfunction [2,[32][33][34][35][36][37][38][39] are involved in the brain damage of GA I patients. It is emphasized that these studies were carried out in animal tissues with normal GCDH activity.…”

Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

“…[21][22][23][24] One implication of these findings is that exposure to high levels of KYNA may begin early in life. It is well established that both acetylcholine and glutamate play critical roles in normal brain development [25][26][27] and that NMDA-Rs and a7 nAChRs are involved in synaptic plasticity and neural development. 4,5 Thus, increases in KYNA concentration and the resulting inhibition of NMDA-Rs and/or a7 nAChRs during critical stages of development could have lasting impacts on brain morphology and/or cognitive function in adulthood.…”

Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice: A possible mechanism for brain injury in glutaric aciduria type I

“…A great body of data have suggested that excitotoxicity [8][9][10][11][12][13][14][15][16][17][18], oxidative stress [19][20][21][22][23][24][25][26][27][28] and mitochondrial dysfunction [29][30][31][32][33][34][35][36][37] are involved in the brain injury of GA I. However, the relevance of energy homeostasis disruption in the brain damage in this disease is not yet established.…”