My laboratory is concerned with the molecular and cellular mechanisms which underlie nerve cell death in the central nervous system. This focus, and my interest in this problem, originated from my postdoctoral work in the 1970s, when I 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, widely confirmed and echoed during the past 25+ years, that "excitotoxic" processes, triggered by an overstimulation of excitatory amino acid receptors, are causally involved in the pathophysiology of several neurological and psychiatric diseases. Over the years and to this day, my laboratory has focussed particularly on the potential role of excitotoxic mechanisms in HD, temporal lobe epilepsy and schizophrenia.

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, schizophrenia, amyotrophic lateral sclerosis, etc.

During the past 25+ 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. As illustrated in the Figure, both QUIN and KYNA 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 function of QUIN and KYNA in the brain.

Ongoing in vivo and in vitro studies are designed 1) to identify possible abnormalities in kynurenine pathway metabolism in excitotoxic brain diseases; 2) to further define the neurobiology of QUIN and KYNA by manipulating kynurenine pathway metabolism with new and specific pharmacological agents and by using molecular biological techniques; and 3) to use novel kynurenergic drugs in order to influence normal and dysfunctional glutamatergic and cholinergic neurotransmission in the central nervous system.