Effect of ornithine alpha ketoglutarate on disturbances of brain metabolism caused by high blood ammonia

Abstract

SUMMARYThe administration of ammonium salts to free ventilated dogs causes an increase in the anaerobic consumption of glucose.Prior and simultaneous administration of the drug ornithine alpha ketoglutarate not only attenuates the rise in blood ammonia but also favourably affects these changes in brain metabolism.In patients with severe hepatic encephalopathy there is a fall in cerebral blood flow and in cerebral oxygen consumption (Fazekas, Ticktin, Ehrmantraut, and Alman, 1956;Posner and Plum, 1960). There is in addition an abnormality in the handling of glucose by the brain which probably precedes the reduction in oxygen utilization (Bianchi Porro, Maiolo, and Della Porta, 1969; James, Nashat, Sampson, Williams, and Gerassini, 1969 The drug ornithine alpha ketoglutarate has been widely used on the continent for a number of years for reducing blood ammonia levels in patients with encephalopathy.Ornithine is a base and alpha ketoglutarate is a diacid. When combined in the proportions 2:1 aneutral salt is obtained.The mechanism of this drug in lowering blood ammonia has recently been outlined by Michel, Oge, and Bertrand (1971). In the liver a molecule of ammonia combines with carbonic anhydride and ATP, carbamyl-phosphate being formed. This then combines with ornithine to form citrulline, which is transformed into arginine on receiving a second NH4+ group. Subsequently under the influence of arginase, urea and ornithine are formed. A total of two molecules of NH4+ have thus been transformed into urea.In the peripheral tissues, alpha ketoglutarate fixes an NH4+ molecule and transforms it into glutamic acid which by collecting a second NH4+ molecule produces glutamine.The fact that ornithine alpha ketoglutarate can lower blood ammonia concentrations in patients with liver disease has already been demonstrated by Michel et al (1971).The purpose of the present experiment was to determine in dogs the way in which ornithine alpha ketoglutarate1 could affect the response of cerebral metabolism to an infusion of an ammonium salt.Three parts of the experiment were planned. First, ammonium bicarbonate was given to dogs in a Ledsome, and Norman (1965) and glucose

Effect of ornithine alpha ketoglutarate (OAKG) on the response of brain metabolism to hypoxia in the dog.

“…Although these changes could be due in part to the recovery from hypoxia, similar changes have previously been shown to be due to OAKG. 6 …”

“…Craniotomy and cannulation of the superior sagittal sinus were carried out as previously described. 6 Sufficient 85…”

Controlled trial of ornithine alpha ketoglutarate (OAKG) in patients with stroke.

“…It is known that elevated CO 2 levels decrease, 3 and lowered CO 2 levels increase, glucose utilization by the brain. 4 The purpose of this study was to evaluate the effect of ornithine alpha ketoglutarate on the anaerobic glycolysis provoked by hypoxia.…”

“…3 The anaerobic glycolysis due to hyperammonemia can be attenuated by the administration of ornithine alpha ketoglutarate. 4 The mechanism by which these changes occur has not been established. Possible mechanisms include the bypassing of the pyruvate decarboxylase stage of glucose breakdown or the replenishing of the intermediates of the citric acid cycle depleted by ammonia.…”

“…8 Since brain glucose consumption falls and oxygen rises after or-nithine alpha ketoglutarate it is likely that the ketoglutarate can pass the blood brain barrier and is utilized. 4 Kobayashi and colleagues 6 have shown experimentally that after cerebral ischemia there is a marked decrease in the concentration of glutarate in the brain. At the same time there is a small rise in glutamine concentration in the brain.…”