Neurochemical Research, VoL 20, No. 12, 1995, pp. 1437-1441 Neurochemical Effects of L-Pyroglutamic Acid Carlos F. de Mello, l,s Diego D. De La Vega, 1 Leandro T. Pizutti, ~ Fabiane P. Lopes, 1 Maribel A. Rubin, 1 Jaime G. Homerich, 2 Carlos R. Melo, 3 Joana E. Somer, 4 Diogo O. Souza, 4 and Moacir Wajner 4 (Accepted August 28, 1995) The effect of L-pyroglutamic acid, a metabolite that accumulates in pyroglutamic aciduria, on different neurochemical parameters was investigated in adult male Wistar rats. Glutamate binding, adenylate cyclase activity and G protein coupling to adenylate cyclase were assayed in the presence of the acid. L-pyroglutamic acid decreased Na+-dependent and Na+-independent glutamate binding. Basal and GMP-PNP stimulated adenylate cyclase activity were not affected by the acid. Further- more, rats received unilateral intrastriatal injections of 10-300 nmol of buffered L-pyroglutamic acid. Vehicle (0.25 M Tris-C1, pH 7.35-7.4) was injected into the contralateral striatum. Neurotoxic damage was assessed seven days after the injection by histological examination and by weighing both cerebral hemispheres. No difference in histology or weight could be identified between hem- ispheres. These results suggest that, although capable of interfering with glutamate binding, pyr- oglutamate did not cause a major lesion in the present model of neurotoxicity. KEY WORDS: Pyroglutamic acid; organic acidemias; neurotoxicity; adenylate cyclase. INTRODUCTION Deficiency of glutathione synthetase is an inherited metabolic disorder characterized by elevated levels of L- pyroglutamic acid in the blood and cerebrospinal fluid, severe metabolic acidosis, tendency toward hemolysis and defective central nervous system function. Patho- logic examination of affected individuals has shown se- lective atrophy of the granule cell layer of the cerebel- lum and focal lesions in the frontoparietal cortex, visual 1 Departamento de Quimica, Centro de Ci~ncias Naturais e Exatas. 2 Departamento de Fisiologia, Centro de Ci~ncias de Safide. 3 Departamento de Patologia, Centro de Ci~ncias da Satide. Universi- dade Federal de Santa Maria, 97119-900, Santa Maria, RS, Brasil. 4 Departamento de Bioquimica, Instimto de Bioci~ncias, Universidade Federal do Rio Grande do Sul, 90050-170, Porto Alegre, RS, Brasil. s Address reprints requests to: Dr. Carlos F. Mello, Universidade Fed- eral de Santa Maria, Departamento de Quimica, Centro de Ci~ncias Naturais e Exatas, Santa Maria, RS, Brasil. Telephone number 055 2261616 Extension 2140; Fax number 055 2261259. 1437 cortex and thalamus. The type and distribution of the lesions resemble those seen in mercury intoxication, which is associated with free radicals production. There- fore, it was suggested that free radical injury may be involved in the neurological damage occurring in this disease (1). On the other hand, patients with pyroglu- tamic aciduria due to 5-oxoprolinase deficiency present tissue levels of the acid similar to those observed in pyr- oglutamic aciduria due to glutathione sinthetase defi- ciency, without significant impairment of body functions (1). Indeed, it has been reported that L-pyroglutamic acid is devoid of neurotoxic activity in vivo (2). Nevertheless, chronic intrastriatal infusion of pyroglutamic acid cause severe cell loss in adult rats, probably by involving ex- citotoxic mechanisms (3). This view is supported by the finding that L-pyroglutamic acid inhibits glutamate up- take by synaptosomes (4), and consequently may cause glutamate accumulation in the extracetlular compart- ment, leading to glutamate-induced excitotoxic damage (5). In this context, it was emphasized in a recent review 0364-3150/95/1200-1437507.50/0 91995PlenumPublishing Corporation