Since diffusion and transport of free ammonia across the cell membrane will affect the pH level of the cell, the more attractive and regulated way of transporting ammonia between the neuronal and the astrocytic compartment is via an amino-acid shuttle, of which there are two: leucine and alanine. The amino acid moves in the opposite direction of glutamine. In the opposite direction of the amino acid, a corresponding molecule is transported; for alanine this molecule is lactate; for leucine, α-ketoisocaproate. The ammonia fixed as part of the glutamate dehydrogenase enzyme reaction in the neurons is transaminated into α-ketoisocaproate to form the branched-chain amino acid leucine, which is exported to the astrocytes, where the process is reversed. α-ketoisocaproate is transported in the other direction. The ammonia produced in neurons is fixed into α-ketoglutarate by the glutamate-dehydrogenase reaction to form glutamate, then transaminated by alanine aminotransferase into lactate-derived pyruvate to form alanine, which is exported to astrocytes. In the astrocytes, this process is then reversed, and lactate is transported in the other direction. Numerous reports have been published indicating that the glutamate/GABA–glutamine cycle is compromised in a variety of neurological disorders and conditions. Biopsies of sclerotic hippocampus tissue from human subjects suffering from epilepsy have shown decreased glutamate–glutamine cycling. Another pathology in which the glutamate/GABA–glutamine cycle might be compromised is Alzheimer's disease; NMR spectroscopy showed decreased glutamate neurotransmission activity and TCA cycling rate in patients suffering from Alzheimer's disease. Hyperammonemia in the brain, typically occurring as a secondary complication of primary liver disease and known as hepatic encephalopathy, is a condition that affects glutamate/GABA–glutamine cycling in the brain. Current research into autism also indicates potential roles for glutamate, glutamine, and/or GABA in autistic spectrum disorders. In the treatment of epilepsy, drugs such as vigabatrin that target both GABA transporters and the GABA metabolizing enzyme GABA-transaminase have been marketed, providing proof of principle for the neurotransmitter cycling systems as pharmacological targets. However, with regard to glutamate transport and metabolism, no such drugs have been developed, because glutamatergic synapses are abundant, and the neurotransmitter glutamate is an important metabolite in metabolism, making interference capable of adverse effects.