Historically, my laboratory was best known for studying the molecular and cellular mechanisms that underlie nerve cell death in the central nervous system. This focus, and my interest in this problem, originated from my postdoctoral work with Dr. Joseph Coyle in the 1970s, when we discovered that an intrastriatal injection of the excitatory amino acid kainate provides a faithful animal model for the neurodegenerative disorder Huntington's Disease (HD; cf. Nature, 263: 244-246, 1976). This led to the idea that endogenous "excitotoxic" processes, triggered by an overstimulation of excitatory amino acid receptors, are causally involved in the pathophysiology of several neurological and psychiatric diseases.
As an offshoot of the excitotoxic hypothesis, we then developed the concept that antagonists of excitatory amino acid ("glutamate") receptors ought to prevent or arrest neurodegeneration and may thus hold promise as novel therapeutic agents for catastrophic brain diseases (cf. Lancet, 2:140-143, 1985). This was verified in several relevant animal models and eventually led to the establishment of anti-excitotoxin-based drug discovery programs in a large number of pharmaceutical houses throughout the world. Several of the resulting drugs are currently undergoing clinical trials for the treatment of stroke, HD, epilepsy, Parkinson’s disease, amyotrophic lateral sclerosis, etc.
During the past 30+ years, most of the work in the laboratory has been concerned with the neurobiology of quinolinate (QUIN) and kynurenate (KYNA), two metabolically related brain constituents with neuroexcitatory (and excitotoxic) and neuroinhibitory (and neuroprotective) properties, respectively. Both QUIN and KYNA (as well as other, metabolically related “kynurenines”) are breakdown products of the so-called kynurenine pathway of tryptophan degradation. Using a combination of biochemical, histological and electrophysiological techniques, we have elaborated many of the characteristics and control mechanisms, which govern the metabolism and function of kynurenines in the brain.
Current studies are designed primarily to explore the role of the kynurenine pathway in the pathophysiology of schizophrenia (SZ) and other serious psychiatric disorders, and to develop fundamentally new therapeutic interventions based on the pharmacological manipulation of brain kynurenines. In this context, we have become especially interested in KYNA, which we found to be causally linked to the cognitive deficits seen in individuals with SZ. This concept is especially relevant since 1) KYNA is an antagonist of both a7 nicotinic and N-methyl-D-aspartate (NMDA) receptors, both of which play critical roles in cognition and brain development; 2) brain and cerebrospinal fluid KYNA levels are significantly increased in SZ; 3) in rodents, experimental KYNA elevations cause cognitive dysfunctions reminiscent of SZ; 4) brain KYNA metabolism is activated by stress and immune stimulation during early development; and 5) prenatal increases in brain KYNA cause an array of SZ-like abnormalities and vulnerabilities in adulthood. Notably, first results indicate that inhibitors of KYNA biosynthesis (“KAT II inhibitors”) show therapeutic efficacy in animal preparations that are believed to be informative for SZ pathophysiology. In close collaboration with clinical researchers at the MPRC, and with the pharmaceutical industry, ongoing basic and clinical work in the laboratory is therefore pioneering the inhibition of KYNA formation as a novel strategy to overcome cognitive impairments in SZ.