Chapter 25 – Astrocytes as Pharmacological Targets in the Treatment of Schizophrenia: Focus on Kynurenic Acid

Abstract The levels of the tryptophan metabolite kynurenic acid (KYNA) are elevated in the brain and cerebrospinal fluid of individuals with schizophrenia and may be causally involved in pathophysiology. This view is based on the ability of KYNA to antagonize the function of α7 nicotinic and N-methyl- d -aspartate receptors, both of which are critical to normal brain development and cognitive processes, and are impaired in schizophrenia. Further support of the “KYNA hypothesis” comes from studies in experimental animals in which even relatively moderate increases in brain KYNA result in a spectrum of biochemical and cognitive abnormalities reminiscent of schizophrenia. Interventions leading to a reduction of cerebral KYNA formation may therefore have therapeutic benefits. Most efforts in this regard have focused on inhibiting the astrocytic enzyme kynurenine aminotransferase II, a major route of KYNA neosynthesis in the brain. Promising preclinical results using specific kynurenine aminotransferase II inhibitors have been obtained recently.