Robert  Schwarcz
 

Robert Schwarcz Ph.D.

Academic Title: Professor
Primary Appointment: Psychiatry
Secondary Appointments: Pediatrics, Pharmacology and Experimental Therapeutics
rschwarc@mprc.umaryland.edu
Location: MPRC, 3-6
Phone: (410) 402-7635
Fax: (410) 747-2434

Personal History

Education

1968: B.Sc. in Chemistry, University of Vienna, Austria.
1974: Ph.D. in Biochemistry, University of Vienna, Austria.

Research Positions

1972-1974: Research Assistant Institute of General Biochemistry University of Vienna, Austria.
1975-1977: Postdoctoral Fellow with J.T. Coyle, M.D., Department of Pharmacology, Johns Hopkins University, Baltimore, Maryland, U.S.A.
1977-1979: Postdoctoral Fellow with K. Fuxe, M.D., Department of Histology, Karolinska Institute, Stockholm, Sweden.
1979-1982: Assistant Professor of Psychiatry, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
1982-1986: Associate Professor of Psychiatry, Maryland Psychiatric Research Center.
1986-present: Professor of Psychiatry, Maryland Psychiatric Research Center.
1986-present: Professor of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
2000-present: Professor of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.

Administrative Positions

1987-present: Director, Neuroscience Program, Maryland Psychiatric Research Center.
1994-present: Deputy Director for Neuroscience, Maryland Psychiatric Research Center.
2004-present: Director of Neuroscience Research, Department of Psychiatry, University of Maryland School of Medicine

Research Interests

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.

Publications

Recent Selected Papers (out of a total of >300)

M.T. Sapko, P. Guidetti, P. Yu, D.A. Tagle, R. Pellicciari and R. Schwarcz: Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: implications for Huntington's disease. Exp. Neurol., 197, 31-40 (2006).

R. Pellicciari, R. Rizzo, G. Costantino, M. Marinozzi, L. Amori, P. Guidetti, H.-Q. Wu and R. Schwarcz: Modulators of the kynurenine pathway of tryptophan metabolism. Synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylalanine, a potent and selective kynurenine aminotransferase II (KAT II) inhibitor. ChemMedChem, 1, 528-531 (2006).

P. Guidetti, G.P. Bates, R.K. Graham, M.R. Hayden, B.R. Leavitt, M.E. MacDonald, E.J. Slow, V.C. Wheeler, B. Woodman and R. Schwarcz: Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol. Dis., 23, 190-197 (2006).

P. Guidetti, G.E. Hoffman, M. Melendez-Ferro, E.X. Albuquerque and R. Schwarcz: Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia, 55, 78-92 (2007).

H.-Q. Wu, A. Rassoulpour and R. Schwarcz: Kynurenic acid leads, dopamine follows: a new case of volume transmission in the brain? J. Neural Transm., 114, 33-41 (2007).

P. Guidetti, L. Amori, M.T. Sapko, E. Okuno and R. Schwarcz: Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J. Neurochem., 102, 103-111 (2007).

C. Lopes, E.F.R. Pereira, H.-Q. Wu, P. Purushottamachar, V. Njar, R. Schwarcz and E.X. Albuquerque: Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha-7 nicotinic receptors. J. Pharmacol. Exp. Therap., 322, 48-58 (2007).

B. Poeggeler, A. Rassoulpour, H.-Q. Wu, P. Guidetti, R.C. Roberts and R. Schwarcz: Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal NMDA neurotoxicity. Neuroscience, 148, 188-197 (2007).

V.H. Brun, S. Leutgeb, H.-Q. Wu, R. Schwarcz, M.P. Witter, E.I. Moser and M.-B. Moser: Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron, 57, 290-302 (2008).

E. Lehrmann, P. Guidetti, A. Love, J. Williamson, E.H. Bertram and R. Schwarcz: Glial activation precedes seizures and hippocampal neurodegeneration in measles virus-infected mice. Epilepsia, 49, Suppl. 2, 13-23 (2008).

F. Giorgini, T. Mueller, W. Kwan, D. Zwilling, J.L. Wacker, S. Hong, L.-C.L. Tsai, C.S. Cheah, R. Schwarcz, P. Guidetti and P.J. Muchowski: Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J. Biol. Chem., 283, 7390-7400 (2008).

F. Rossi, R. Schwarcz and M. Rizzi: Curiosity to kill the KAT (kynurenine aminotransferase): structural insights into brain kynurenic acid synthesis. Curr. Opin. Struct. Biol., 18, 748-755 (2008).

L. Amori, H.-Q. Wu, M. Marinozzi, R. Pellicciari, P. Guidetti and R. Schwarcz: Specific inhibition of kynurenate synthesis enhances extracellular dopamine levels in the rodent striatum. Neuroscience, 159, 196-203 (2009).

A. Zmarowski, H.-Q. Wu, J.M. Brooks, M.C. Potter, R. Pellicciari, R. Schwarcz and J.P. Bruno: Astrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine release. Eur. J. Neurosci., 29, 529-538 (2009).

L. Amori, P. Guidetti, R. Pellicciari, Y. Kajii and R. Schwarcz: On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J. Neurochem., 109, 316-325 (2009).




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