dizocilpine-maleate and Ornithine-Carbamoyltransferase-Deficiency-Disease

Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl-D-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.

Topics: Acetylcarnitine; Adenosine Triphosphate; Aging; Amino Acid Metabolism, Inborn Errors; Ammonia; Animals; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression Regulation, Developmental; Kinetics; Mice; Mice, Mutant Strains; Nootropic Agents; Ornithine Carbamoyltransferase Deficiency Disease; Receptors, N-Methyl-D-Aspartate; Reference Values; Synaptic Membranes

Alterations of excitatory amino acid neurotransmitters have previously been described in brain in congenital ornithine transcarbamylase (OTC) deficiency. In order to further elucidate the role of the glutamatergic neurotransmitter system in OTC deficiency, densities of binding sites for [3H]MK801, an NMDA receptor antagonist ligand were measured by quantitative receptor autoradiography in the brains of chronically hyperammonemic sparse-fur mice (spf), mutant mice with a congenital defect of OTC. [3H]MK801 binding site densities were significantly reduced by up to 57% (p < 0.01) in 16 out of 17 brain regions of OTC-deficient mice. Such changes could result from either neuronal cell loss in these animals or from "down-regulation" of these sites as a consequence of exposure to increased extracellular concentrations of glutamate or quinolinic acid, two known endogenous NMDA receptor ligands previously found to be increased in brain in chronic hyperammonemic syndromes. Reduced NMDA receptor densities in congenital OTC deficiency could represent an adaptive mechanism of protection against further excitotoxic brain injury.

Topics: Animals; Autoradiography; Binding Sites; Brain; Dizocilpine Maleate; Female; Hair; Male; Mice; Mice, Mutant Strains; Ornithine Carbamoyltransferase Deficiency Disease; Quaternary Ammonium Compounds; Receptors, N-Methyl-D-Aspartate; Tritium