Influence of some biological pyrimidines on the succinate cycle during and after cerebral ischemia

Abstract

Some cortical metabolites (glycogen, glucose, glucose-6-phosphate, pyruvate, lactate, α-ketoglutarate, succinate, fumarate. malate, citrate, glutamate, glutamine, alanine, NH 4 +) were studied in rat brain after 5 min of complete compression ischemia, as well as after 15 min of recirculation following 5 min of ischemia. These two conditions (ischemia and post ischemia restitution) were induced in control animals and in rats pretreated 1 hr before by an intraperitoneal injection of 120 mg·kg −1 of some biological pyrimidines (uridine, cytidine and uridine disphosphate glucose). At the cerebral level total complete ischemia induced the: (a) drop of substrates and of glycolytic intermediates, consistent with the increase of lactate and redox state; (b) increase of succinate and alanine; (c) decrease of malate and fumarate; and (d) depletion of α-ketoglutarate. Some of these events may be regarded as the expression of the activation of the succinate cycle which contributed by approx. 10 per cent to the release of anaerobic energy during cerebral ischemia. Pretreatment with the tested pyrimidines did not modify this cerebral biochemical pattern. During post-ischemic recovery, cerebral parameters tended to normalize, except for a further increase in alanine production (as an expression of the activation of the alanine aminotransferase reaction) with conversion of pyruvate into α-ketoglutarate available for the ammonia-detoxicating processes (amination to glutamate and amidation to glutamine). During post-ischemic recovery, pretreatment with cytidine was poorly active. Pretreatment with uridine decreased glucose, glucose-6-phosphate and pyruvate cerebral concentrations, while succinate and alanine were increased. This latter effect was also present in the case of pretreatment with uridine diphosphate glucose. However, this substance increased the cerebral concentration of glycogen and decreased those of fumarate and malate. The different biochemical actions of uracyl derivatives are discussed with regard to their biological effects.