Kynurenines and Glutamate: Multiple Links and Therapeutic Implications

Glutamate is firmly established as the major excitatory neurotransmitter in the mammalian brain and is actively involved in most aspects of neurophysiology. Moreover, glutamatergic impairments are associated with a wide variety of dysfunctional states, and both hypo- and hyperfunction of glutamate have been plausibly linked to the pathophysiology of neurological and psychiatric diseases. Metabolites of the kynurenine pathway (KP), the major catabolic route of the essential amino acid tryptophan, influence glutamatergic activity in several distinct ways. This includes direct effects of these "kynurenines" on ionotropic and metabotropic glutamate receptors or vesicular glutamate transport, and indirect effects, which are initiated by actions at various other recognition sites. In addition, some KP metabolites affect glutamatergic functions by generating or scavenging highly reactive free radicals. This review summarizes these phenomena and discusses implications for brain physiology and pathology.