Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity

Ammonia enters the brain by diffusion from the blood or cerebrospinal fluid , or is formed in situ from the metabolism of endogenous nitrogen-containin g substances. Despite its central importance in nitrogen homeostasis, exces s ammonia is toxic to the central nervous system and its concentration in t he brain must be kept low. This is accomplished by the high activity of glu tamine synthetase, which is localized in astrocytes and which permits effic ient detoxification of incoming or endogenously generated ammonia. The loca tion also permits the operation of an intercellular glutamine cycle. In thi s cycle, glutamate released from nerve terminals is taken up by astrocytes where it is converted to glutamine. Glutamine is released to the extracellu lar fluid to be taken up into the nerve cells, where it is converted back t o glutamate by the action of glutaminase. Most extrahepatic organs lack a c omplete urea cycle, and for many organs, including the brain, glutamine rep resents a temporary storage form of waste nitrogen. As such, glutamine was long thought to be harmless to the brain. However, recent evidence suggests that excess glutamine is neurotoxic. Hyperammonemic syndromes (e.g., liver disease, inborn errors of the urea cycle, Reye's disease) consistently cau se astrocyte pathology. Evidence has been presented that hyperammonemia res ults in increased formation of glutamine directly in astrocytes, thereby ge nerating an osmotic stress to these cells. This osmotic stress results in i mpaired astrocyte function, which in turn leads to neuronal dysfunction. In this review a brief overview is presented of the role of glutamine in norm al brain metabolism and in the pathogenesis of hyperammonemic syndromes. (C ) 2001 Wiley-Liss, Inc.