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Robert Schwarcz, PhD

Academic Title:

Professor

Primary Appointment:

Psychiatry

Secondary Appointment(s):

Pediatrics, Pharmacology

Location:

MPRC, 3-6

Phone (Primary):

(410) 402-7635

Phone (Secondary):

(443) 851-3332 (cell)

Fax:

(410) 747-1157

Education and Training

 

1968:  B.Sc. in Chemistry, University of Vienna, Austria

 

1974:  Ph.D. in Biochemistry, University of Vienna, Austria

 

1975 - 1977:    Postdoctoral Fellow with J.T. Coyle, M.D., Department of Pharmacology, Johns Hopkins University, Baltimore, Maryland, USA

 

1977 - 1979:    Postdoctoral Fellow with K. Fuxe, M.D., Department of Histology, Karolinska Institute, Stockholm, Sweden

 

Biosketch

NAME: SCHWARCZ, ROBERT

eRA COMMONS USER NAME (credential, e.g., agency login): SCHWARCZ

POSITION TITLE: Professor of Psychiatry, Pharmacology and Pediatrics

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY
University of Vienna PhD 1974 Biochemistry
Johns Hopkins University Postdoctoral Fellow 1977 Neuropharmacology
Karolinska Institute Postdoctoral Fellow 1979 Histology

 

A. PERSONAL ST AT EMENT

 

During the past 35 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 are products of the kynurenine pathway of tryptophan degradation. Using a combination of biochemical, histological, behavioral 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 major neurological and psychiatric diseases, and in relevant animal models; 2) to further define the neurobiology of QUIN and KYNA in animals by manipulating the kynurenine pathway pharmacologically and genetically; and 3) to develop and use novel kynurenergic drugs in order to normalize functional impairments in the central nervous system.  My laboratory currently consists of 8 team members (senior/postdoctoral scientists, students and research assistants), who focus mainly on work with experimental animals and on studies with clinical samples provided by investigators at my own institution and by selected external collaborators.

 

B. Positions and Honors

 

Positions and Employment

 

1979 - 1982     Assistant Professor of Psychiatry, University of Maryland Baltimore, Maryland Psychiatric

                        Research Center

1982 - 1986     Associate Professor of Psychiatry, University of Maryland Baltimore, Maryland Psychiatric

                        Research Center

1986 -                          Professor of Psychiatry, University of Maryland Baltimore, Maryland Psychiatric Research

                        Center

 

Selected Honors

 

1994                  Merck Neuroscience Lecturer, British Pharmacological Society

1998                  4th Hillarp Lecture, Society for Neuroscience

2001                  Dezsö Miskolczy Memorial Lecturer, University of Szeged, Hungary

2007                  Regents' Faculty Award, University System of Maryland

2007                  Epilepsy Research Award, ASPET

2009                  Foreign Adjunct Professor, Karolinska Institute (elected)

2015                 Musajo Medal, International Society for Tryptophan Research

 

Selected other Experience and Professional Memberships

 

1987 - 1993     Scientific Council, Huntington's Disease Society of America

1990 - 1994     Member, Neurological Sciences 2, NINDS Study Section

1988                Member, ACNP (Fellow, 2000)

2001 - 2003 and 2006 - 2008  Member, ACNP Program Committee

2007                            Chair, ACNP Program Committee

2007 - 2008     Member, Program Committee, American Epilepsy Society

2007 - 2009     Member, Research Initiative Fund Review Committee, American Epilepsy Society

2008 - 2018     Member, Board of Trustees, Medical University of Vienna

2009 -                          Member, Scientific Council, Brain & Behavior Research Foundation (NARSAD)

2009 - 2011     Member, ACNP Liaison Commitee

2012 - 2014     Member, ACNP Ethics Committee

2016 - 2018     Member, ACNP Awards Committee

 

C. Contributions to science

1. During my postdoctoral period, first under the mentorship of Dr. Joseph Coyle (Johns Hopkins University), then with Drs. Kjell Fuxe and Tomas Hökfelt (Karolinska Institute), I was concerned mainly with the molecular and cellular mechanisms that underlie nerve cell death in the central nervous system. I showed that an intrastriatal injection of the excitatory amino acid kainate provides a faithful animal model for the neurodegenerative disorder Huntington's Disease. In Stockholm, I discovered that ibotenic acid, another excitatory amino acid receptor agonist, duplicates the selective toxic effects of kainate in the striatum. Compared to kainate, however, ibotenate turned out to be a superior experimental lesioning tool, which is being used to this day in neuroscience laboratories throughout the world. These studies with kainate and ibotenate led to the idea, widely confirmed and echoed during the past 35+ years, that "excitotoxic" processes, triggered by an overstimulation of excitatory amino acid receptors, are causally involved in the pathophysiology of several major neurological diseases.

a. Coyle JT, Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature. 1976 Sep 16;263(5574):244-6. PubMed PMID: 8731.

b. Schwarcz R, Creese I, Coyle JT, Snyder SH. Dopamine receptors localised on cerebral cortical afferents to rat corpus striatum. Nature. 1978 Feb 23;271(5647):766-8. PubMed PMID: 625348.

c. Schwarcz R, Fuxe K, Agnati LF, Hökfelt T, Coyle JT. Rotational behaviour in rats with unilateral striatal kainic acid lesions: a behavioural model for studies on intact dopamine receptors. Brain Res. 1979 Jul 20;170(3):485-95. PubMed PMID: 37986.

d. Schwarcz R, Hökfelt T, Fuxe K, Jonsson G, Goldstein M, Terenius L. Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study. Exp Brain Res. 1979. Oct ;37(2):199-216. PubMed PMID: 40808.

2. In the early 1980s, at the beginning of my career as an independent investigator, I 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. I verified this idea in several relevant neurological disease models. In the following years, this breakthrough discovery led to the establishment of anti-excitotoxin-based drug development programs in most major pharmaceutical companies.

a. Schwarcz R, Collins JF, Parks DA. Alpha-amino-omega-phosphonocarboxylates block ibotenate but not kainate neurotoxicity in rat hippocampus. Neurosci Lett. 1982 Nov 16;33(1):85-90. PubMed PMID: 6130496.

b. Aldinio C, French ED, Schwarcz R. The effects of intrahippocampal ibotenic acid and their blockade by (-2-amino-7-phosphonoheptanoic acid: morphological and electroencephalographical analysis. Exp Brain Res. 1983;51(1):36-44. PubMed PMID: 6309547.

c. Schwarcz R, Collins J, Curry K., inventors. Aminoacid Isomers, Their Production and Their Medicinal Use. USA 4,483,853. 1984 November 20.

d. Schwarcz R, Meldrum B. Excitatory aminoacid antagonists provide a therapeutic approach to neurological disorders. Lancet. 1985 Jul 20;2(8447):140-3. PubMed PMID: 2862329.

3. Based on my hypothesis that endogenous excitotoxins may play a role in the pathophysiology of human brain disorders, I discovered, in 1983, that the tryptophan metabolite quinolinic acid (QUIN) triggers specific neurodegenerative events in the mammalian brain. I subsequently identified QUIN as a regular constituent of the human brain, described and characterized its metabolic enzymes in the brain and found, unexpectedly, that the metabolite was produced in, and released from, glial cells rather than neurons. This led me to propose in the 1980s, i.e. at a time when glial cells were still considered “brain glue” or at best suppliers of nutrition and energy to neurons, that glia-derived QUIN, by targeting glutamate receptors on nerve cells, may play an important role in neuronal function and dysfunction. My interest in the neurobiology of QUIN then prompted me to investigate the effects of a related tryptophan metabolite, kynurenic acid (KYNA). I first showed that KYNA exists normally in the mammalian brain and possesses pronounced neuroprotective and anticonvulsant properties. I then demonstrated that KYNA’s biosynthetic enzymes in the brain reside preferentially in astrocytes. Further characterization of KYNA metabolism revealed that one of these enzymes, which we named kynurenine aminotransferase (KAT) II, singularly controls the function of neuroactive KYNA.

a. Schwarcz R, Whetsell WO Jr, Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 1983 Jan 21;219(4582):316-8. PubMed PMID: 6849138.

b. Köhler C, Okuno E, Flood PR, Schwarcz R. Quinolinic acid phosphoribosyltransferase: preferential glial localization in the rat brain visualized by immunocytochemistry. Proc Natl Acad Sci USA. 1987 May;84(10):3491-5. PubMed PMID: 3472219; PMCID: PMC304897.

c. Turski WA, Gramsbergen JB, Trait ler H, Schwarcz R. Rat brain slices produce and liberate kynurenic acid upon exposure to L-kynurenine. J Neurochem. 1989 May;52(5):1629-36. PubMed PMID: 2709016.

d. Okuno E, Nakamura M, Schwarcz R. Two kynurenine aminotransferases in human brain. Brain Res. 1991 Mar 1;542(2):307-12. PubMed PMID: 2029638.

4. Using both genetic approaches and new pharmacological tools designed together with my postdocs, students and collaborators nationally and internationally, I went on to show that selective attenuation of KATII activity has profound effects on the fate and function of the classic neurotransmitters glutamate, dopamine, acetylcholine and – as shown more recently – GABA. Originating from astrocytes, KYNA is therefore a new, chemical messenger with unique neuromodulatory properties. This insight led me and others to propose a role of (fluctuations in) astrocyte-derived KYNA in the control of physiological processes ranging from neurotransmitter release and mechanisms involved in synapse formation and neuronal plasticity to motor and cognitive behaviors. Validation of this concept, in several cases using specific KAT II inhibitors first tested in my laboratory, has now been provided by distinguished scientists worldwide.

a. Rassoulpour A, Wu HQ, Ferre S, Schwarcz R. Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem. 2005 May;93(3):762-5. PubMed PMID: 15836634.

b. Pellicciari R, Rizzo RC, Costantino G, Marinozzi M, Amori L, Guidetti P, Wu HQ, Schwarcz R. Modulators of the kynurenine pathway of tryptophan metabolism: synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylalanine, a potentand selective kynurenine aminotransferase II (KATII) inhibitor. ChemMedChem. 2006 May;1(5):528-31. PubMed PMID: 16892388.

c. Potter MC, Elmer GI, Bergeron R, Albuquerque EX, Guidetti P, Wu HQ, Schwarcz R. Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology. 2010 Jul;35(8):1734-42. PubMed PMID: 20336058; PubMed Central PMCID: PMC3055476.

d. Beggiato S, Tanganelli S, Fuxe K, Antonelli T, Schwarcz R, Ferraro L. Endogenous kynurenic acid regulates extracellular GABA levels in the rat prefrontal cortex. Neuropharmacology. 2014 Jul;82:11-8. PubMed PMID: 24607890.

5. During the past 10-15 years, it became clear that drugs which are able to normalize the balance between QUIN and KYNA in the brain hold great promise for the treatment of major human brain diseases, including Parkinson’s disease, Alzheimer’s disease, depressive disorders, schizophrenia and drug abuse. Depending on the nature of the underlying disease process, QUIN synthesis inhibitors or KATII inhibitors are currently considered prime candidates for clinical interventions. Our recent papers, as well as studies by other investigators in both academia and industry, attest to the feasibility of This new approach and have provided impressive proof-of-concept data in relevant disease models.

a. Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, Muchowski PJ. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011 Jun 10;145(6):863-74. PubMed PMID: 21640374; PubMed Central PMCID: PMC3118409.

b. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012 Jul;13(7):465-77. PubMed PMID: 22678511; PubMed Central PMCID: PMC3681811.

c. Justinova Z, Mascia P, Wu HQ, Secci ME, Redhi GH, Panlilio LV, Scherma M, Barnes C, Parashos A, Zara T, Fratta W, Solinas M, Pistis M, Bergman J, Kangas BD, Ferré S, Tanda G, Schwarcz R, Goldberg SR. Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid. Nat Neurosci. 2013 Nov;16(11):1652-61. PubMed PMID: 24121737; PubMed Central PMCID: PMC3835353.

d. Wu HQ, Okuyama M, Kajii Y, Pocivavsek A, Bruno JP, Schwarcz R. Targeting kynurenine aminotransferase II in psychiatric diseases: promising effects of an orally active enzyme inhibitor. Schizophr Bull. 2014 Mar;40 Suppl 2:S152-8. PubMed PMID: 24562494; PubMed Central PMCID: PMC3934402.

Complete List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/robert.schwarcz.1/bibliography/47299289/public/?sort=date&direction=ascending

 

D. Research Support

Ongoing Research Support

 

P50 MH103222, NIMH, SCHWARCZ, ROBERT                                                                         2014/05/09-2019/02/28

Kynurenic Acid and Cognitive Abnormalities in Schizophrenia

The translational Conte Center is designed to provide new insights into the role of the tryptophan metabolite kynurenic acid in cognition in rodents and humans, and to examine inhibition of kynurenic acid formation as a novel strategy to overcome cognitive impairments. 

Role: PI

 

P50 MH103222 NIMH, SCHWARCZ ROBERT                                                           2017/06/01-2019/02/28                                                                                Supplement NeuroBioBank

                    

VistaGen Therapeutics, SCHWARCZ, ROBERT                                                         2017/07/01-2018/06/30

 4-Cl-Kynurenine (AV-101) vs. Kynurenine: Effects on Neurogenesis in the Rat Brain

Comparison of the effects of prolonged treatment with a prodrug of a NMDA receptor antagonist and kynurenine on neurogenesis in the adult rat brain

Role: PI

 

 

Research Support completed within the past three years

Research Award, Lundbeck Research, USA, SCHWARCZ, ROBERT                                              2013/11/01-2016/10/31

Inflammation, Kynurenines and Neurological Disease

Use inflammation-based animal models to predict efficacy of interventions targeting the kynurenine pathway in neurodegenerative disease

Role: PI

 

R21 MH099345-02, NIMH, SCHWARCZ, ROBERT                                                                                              2014/09/09-2016/07/31

An NMDA Glycine Site Antagonist for the Treatment of Major Depressive Disorder

Validated tests in rodent s are used to determine the anti-depressant-like capacity and side-effect profile of 4-chlorokynurenine, a brain-penetrant pro-drug of a selective NMDA receptor ant agonist

Role: co-PI

 

Research Award, Mitsubishi-Pharma, Japan, SCHWARCZ, ROBERT                                        2014/03/01-2016/02/28

Development of novel, Systemically Active KATII Inhibitors

Evaluation of newly synthesized compounds for their ability to inhibit kynurenic acid synthesis in rat s

Role: PI

 

R01NS025296-23, NINDS, SCHWARCZ, ROBERT                                                                                       1987/07/01-2014/04/30

Nicotinic Receptors: Role in Hippocampal Synaptic Function

This project tested the interact ions between kynurenic acid and hippocampal nicotinic receptors

Role: co-I

R01 MH083729-05, NIMH, SCHWARCZ, ROBERT                                                                                                               2009/12/01-2015/11/30

Endogenous Kynurenic Acid Modulates Prefrontal ACh Levels and Cognitive Behavior

This project investigates the role of kynurenic acid in the control of cognitive processes in rats

Role: co-PI

 

 

 

 

 

 

 

 

Research/Clinical Keywords

Cognition, Excitotoxicity, Glutamate, Kynurenic acid, Neurodegenerative diseases, Neuroprotection, Quinolinic acid, Schizophrenia, Tryptophan

Highlighted Publications

D. Zwilling, S.-Y. Huang, K.V. Sathyasaikumar, F.M. Notarangelo, P. Guidetti, H.-Q. Wu, J. Lee, J. Truong, Y. Andrews-Zwilling, E.W. Hsieh, J.Y. Louie, T. Wu, K. Scearce-Levie, C. Patrick, A. Adame, F. Giorgini, S. Moussaoui, G. Laue, A. Rassoulpour, G. Flik, Y. Huang, J.M. Muchowski, E. Masliah, R. Schwarczand P.J. Muchowski:  Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.  Cell, 145, 863-874 (2011).

  

R. Schwarcz, J.P. Bruno, P.J. Muchowski and H.-Q. Wu: Kynurenines in the mammalian brain: when physiology meets pathology.  Nature Rev. Neurosci., 13, 465-477 (2012).

 

Z. Justinova, P. Mascia, H.-Q. Wu, M.E. Secci, G.H. Redhi, L.V. Panlilio, M. Scherma, C. Barnes, A. Parashos, T. Zara,W. Fratta,M. Solinas, M. Pistis,J. Bergman, B.D. Kangas,S. Ferré, G. Tanda, R. Schwarczand S.R. Goldberg: Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.  Nature Neurosci., 16, 1652-1661 (2013).

 

J. Chiappelli, A. Pocivavsek, K.L. Nugent, F.M. Notarangelo, P. Kochunov, L.M. Rowland, R. Schwarcz and L.E. Hong:  Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. JAMA Psychiatry, 71, 761-768 (2014).

 

C. Breda, K.V. Sathyasaikumar, S.S. Idrissi, F.M. Notarangelo, J.G. Estranero, G.G.L. Moore, E.W. Green, C.P. Kyriacou, R. Schwarcz and F. Giorgini:  Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.  Proc. Natl. Acad. Sci. (U.S.A.), 113, 5435-5440 (2016).

Clinical Specialty Details

 

Epilepsy, Huntington's disease, Parkinson's disease, Major depressive disorders, Schizophrenia

Awards and Affiliations

1972 - 1974:    Research Assistant, Institute of General Biochemistry, Vienna, Austria

 

1975 - 1977:    Postdoctoral Fellow with J.T. Coyle, M.D., Department of Pharmacology, Johns Hopkins University, Baltimore, Maryland, USA

 

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, USA

 

1982 - 1986:    Associate Professor of Psychiatry, Maryland Psychiatric ResearchCenter

 

1986 -         :      Professor of Psychiatry, Maryland Psychiatric ResearchCenter

 

1986 -        :      Professor of Pharmacology, University of MarylandSchool of Medicine

 

2000 -       :      Professor of Pediatrics, University of MarylandSchool of Medicine

 

2009-        :       Adjunct Professor (elected), Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

 

Friedrich Merz Professor, University of Frankfurt, Germany (1993)

Merck Neuroscience Lecturer, British Pharmacological Society (1994)

Faculty Researcher of the Year, University of Maryland (1997)

4th Hillarp Lecture, Society for Neuroscience (1998)

Visiting Professor, University of Perugia, Italy (2000, 2007)

Dezsö Miskolczy Memorial Lecturer, University of Szeged, Hungary (2001)

ASPET Epilepsy Research Award (2007)

University System of Maryland Regents’ Faculty Award (2007)

Musajo Medal – International Tryptophan Society (2015)

Karolinska Institute, Stockholm, Sweden

Grants and Contracts

1.         "Platelets, Glutamate and Huntington's Disease": 11/1/79 - 12/31/80; The Wills Foundation; $15,000.

 

2.         "Kainic Acid and Striatal Dopamine Turnover": 01/01/80 - 12/31/80; NIMH small grant; $10,638.

 

3.         "Properties of Synthetic and Degradative Enzymes for Glutamate in HD":  7/1/80 - 12/31/81; The Wills Foundation; $15,000.

 

4.         "Neuroexcitatory Amino Acid Mechanisms in vivo and in vitro": 1/1/81 - 12/31/83; NINCDS grant; $149,550.

 

5.         "Kainic Acid, Hippocampus and Temporal Lobe Epilepsy": 8/1/81 - 7/31/84; NINCDS grant; $137,515.

 

6.         "GMl and Hippocampal Lesions": 8/1/82 - 7/31/85; FIDIA Research Laboratories; $31,330.

 

7.         "Excitotoxic Amino Acids: Antagonism in vivo and in vitro": 2/1/83 - 1/31/85; NATO grant for international colla­boration in research; $10,400.

 

8.         "Synthesis of (-)2-Amino-7-Phosphonoheptanoic Acid": 4/1/83 - 6/30/83; Committee to Combat Huntington's Disease; $5,000.

 

9.         "Neuroexcitatory Amino Acid Mechanisms in vivo and in vitro": 1/1/84 - 12/31/86; NINCDS grant; $265,450.

 

10.       "Quinolinic Acid and Seizure Disorders" 8/1/84 - 7/31/87; NINCDS grant; $209,417.

 

11.       "Quinolinic Acid and Parkinson's Disease": 7/1/85 - 6/30/86; American Parkinson Disease Association; $20,000.

 

12.       "Quinolinic Acid and Parkinson's Disease/II": 7/1/86 - 6/30/87; American Parkinson Disease Association: $20,000.

 

13.       "Neuroexcitatory Amino Acid Mechanisms in vivo and in vitro": 1/1/87 - 12/31/89; NINCDS grant; $504,613.

 

14.       "Quinolinic Acid and Seizure Disorders": 8/1/87 - 7/31/90; NINCDS grant; $335,643.

 

15.       "NeuroscienceCenter for Research in Schizophrenia" (W.T. Carpenter, P.I.); subproject "Neuroleptic Treatment and Brain Kynurenines": 3/1/89 - 2/28/94; NIMH grant; $220,000.

 

16.       "Quinolinic Acid and Seizure Disorders": 9/24/90 - 9/23/93; NINDS grant; $601,502.

 

17.       "Neuroexcitatory Amino Acid Mechanisms in vivo and in vitro": 1/1/90 - 12/31/94; NINDS grant; $1,187,086.

 

18.       "Neuroactive Kynurenines": 1/1/92 - 12/31/94; Pharmacia/Farmitalia (Milano); $304,500.

 

19.       "Quinolinate Synthesis Inhibitors": 1/1/91 - 12/31/94; ASTRA ArcusAB (Södertälje); $114,333.

 

20.       "Neuroactive Kynurenines": 1/1/95 - 12/31/95; Pharmacia (Milano); $150,000.

 

21.       "Neuroactive Kynurenines": 1/1/96 - 12/31/96; Pharmacia (Milano); $150,000.

 

22.       "Kynurenines, Glia and Epilepsy": 4/1/94 - 1/31/98; NINDS grant; $926,068.

 

23.        "Neuroactive Kynurenines": 1/1/97 - 12/31/97; Pharmacia & Upjohn (Milano); $150,000.

 

24.       "Neuroexcitatory Amino Acid Mechanisms in vivo and in vitro": 1/1/95 - 12/31/99; NINDS grant; $1,069,605.

 

25.       "Kynurenines, Glia and Epilepsy": 2/1/98 - 1/31/03; NINDS grant; $1,027,158.

 

26.       "Metabolic and Developmental Aspects of Mental Retardation" (H.R. Zielke, P.I.); subproject "Kynurenic Acid Formation & Function During Development": 5/1/98 - 4/30/03; NICHD grant; $513,665.

 

27.        “Kynurenic Acid, Nicotine and Schizophrenia”: 5/1/02 - 4/30/03; NARSAD Distinguished Investigator grant; $99,746.

 

28.        “The Role of Kynurenic Acid in Development”: 5/1/01 - 7/1/03;  NRSA grant; $50,933.

 

29.         “Kynurenine 3-hydroxylase as a Target for Drug Development”: 11/1/01 - 10/31/03; Newron (Milano); $170,000.

 

30.          “Quinolinic Acid in HD Mouse models”:  4/1/04 – 9/30/04; HighQ-Hereditary Disease Foundation; $67,500.

 

31.          “Chronic Interventions to Influence Brain Kynurenine Pathway Metabolism in Mice”:  7/1/05-12/31/05; HighQ Foundation; $74,500.

 

32.          “Kynurenic Acid Synthesis and Schizophrenia”:  7/1/05-3/31/08; Mitsubishi Pharma; $185,000.

 

33.          “Nicotinic Receptor: Role in Hippocampal Synaptic Function” (E.X. Albuquerque, P.I.): 8/1/02-7/31/07; NINDS grant; $200,000.

 

34.          "Kynurenines, Glia and Epilepsy”: 7/1/03 - 6/30/07; NINDS grant; $1,160,168.

 

35.          “Imaging Tryptophan Metabolism in Children with Epilepsy” (D.C. Chugani, P.I.): 12/01/03-11/30/08; NINDS grant; $66,000.

 

36.          "Metabolic and Developmental Aspects of Mental Retardation" (H.R. Zielke, P.I.); subproject "Kynurenic Acid Formation & Function During Development": 4/1/04-3/31/09; NICHD grant; $675,000.

 

37.           “The Kynurenine Pathway in Huntington’s Disease”:  11/01/06-10/31/08; HighQ Foundation; $550,000.

 

38.           “Kynurenine Pathway Metabolism: In Vivo Drug Effects”: 5/15/08-5/14/09;  CHDI Inc.; $110,402.

 

39.            “Kynurenic Acid Synthesis and Schizophrenia”: 9/1/08-8/31/09; Mitsubishi-Tanabe; $85,000.

 

40.            “Kynurenine Pathway Enzymes in the Human Brain in Huntington’s Disease”: 9/1/09-8/31/10; CHDI Inc.; $175,853.

 

41.             “Understanding Effects of Chronically Manipulated Brain Kynurenate Levels on Neural Systems”:  9/1/09-8/31/10; Mitsubishi-Tanabe; $95,000.

 

42.              “Validation of KAT II as a Therapeutic Target for Schizophrenia”:  7/1/2010- 6/30/2012; Bristol-Myers-Squibb Innovation grant; $230,000.

 

43.               “Understanding Effects of Neurochemical Consequences Caused by Systemic Manipulation of the Brain Kynurenine Pathway from Viewpoints of Psychiatric Symptoms”:  8/1/10-3/31/13; Mitsubishi-Tanabe;                            $275,000.

 

44.              ”The Role of Microglia and the Kynurenine Pathway in Huntington’s Disease" (co-P.I. with P.J. Muchowski):  3/1/09-2/28/14; NINDS grant; $625,000.

 

45.               “Proteopathies of the Aging Central Nervous System“ (L. Mucke, P.I.); subproject “Kynurenines, Microglia and Alzheimer’s Disease” (co-P.I. with P.J. Muchowski): 8/1/08-7/31/13; NIA grant; $265,000.

 

46.               “Nicotinic Receptor: Role in Hippocampal Synaptic Function” (co-P.I. with E.X. Albuquerque): 8/1/08-7/31/13; NINDS grant; $337,500.

 

47.               “Endogenous Kynurenic Acid Modulates Prefrontal ACh Levels and Cognitive Behavior” (co-P.I. with J.P. Bruno):  12/1/09-11/30/14; NIMH grant; $1,250,000.

 

48.               “An NMDA Glycine Site Antagonist for the Treatment of Major Depressive Disorder” (co-P.I. with T.D. Gould): 9/9/13-9/8/15; NIMH grant; $275,000.

 

49.                “Development of Novel, Systemically Active KAT II Inhibitors”: 3/1/2014 - 2/28/2016; Mitsubishi-Pharma; $200,000.

 

50.                “Inflammation, Kynurenines and Psychiatric Diseases”: 9/1/13-8/31/16; Lundbeck Research USA; $708,000.

 

51.                “Kynurenic Acid and Cognitive Abnormalities in Schizophrenia”: 6/11/2015- 6/10/2016; NIMH Supplement sex differences (Conte Center); $100,000.                                                           

 

52.                “Kynurenic Acid and Cognitive Abnormalities in Schizophrenia”: 4/1/2014-3/31/2019; NIMH grant (ConteCenter); $10,712,744.

 

53.                “Kynurenic Acid and Cognitive Abnormalities in Schizophrenia”: 6/1/2017-3/31/2019; NIMH Supplement NeuroBioBank (Conte Center); $206,000.

 

54.                “4-Cl-Kynurenine (AV-101) vs. Kynurenine: Effects on Neurogenesis inthe Rat Brain“: 7/1/2017-6/30/2018; VistaGen Therapeutics; $146,826.

 

In the News

United States Patents (+ year of original filing)

 

1.  "Aminoacid Isomers, their Production and their Medicinal Use" (with J.F. Collins and K. Curry) (1981) US Patent 4,483,853 (issued November 20, 1984)

 

2.  "NMDA Antagonists" (with M. G. Palfreyman, I.A. McDonald, F. G. Salituro and B.M. Baron) (1991) US Patent 5,470,870 (issued November 28, 1995)

 

3.  “New Compounds” (with S.K.M. Björk, B.K. Carpenter, B.K. Gotthammar, M.T. Linderberg, J.P. Luthman and K.M.I. Persson) (1994) US Patent 5,523,475 (issued June 4, 1996)

 

4.  “3-Hydroxyanthranilic Acid Derivatives” (with S.K.M. Björk, B.K. Gotthammar, M.T. Linderberg, J.P. Luthman and K.M.I. Persson) (1995) US Patent 5,661,183 (issued August 26, 1997)

 

5.  “Compounds” (with S.K.M. Björk, B.K. Gotthammar, M.T. Linderberg, J.P. Luthman and K.M.I. Persson) (1996) US Patent 5,688,945 (issued November 18, 1997)

 

6.  "Substituted Kynurenines and Process for their Preparation" (with M. Varasi, A. Della   Torre, C. Speciale and A. Bianchetti) (1995) US Patent 5,786,508 (issued July 28, 1998)

 

7.  "Hydroxylated Anthranilic Acid Derivatives" (with S.K.M. Björk, B.K. Gotthammar, M.T. Linderberg, J.P. Luthman, K.M.I. Persson and B.K. Carpenter)  (1995) US Patent 5,883,129 (issued March 15, 1999)


8.  "Recombinant KAT Enzyme and Process for its Preparation" (with L. Benatti, J. Breton, C. Speciale, E. Okuno and M. Mosca) (1997) U.S. Patent 6,136,572 (issued October 24, 2000)

 

9.  “4-Sulfonyl-substituted Benzoylalanine Derivatives Useful as Kynurenine-Aminotransferase Inhibitors” (with R. Pellicciari and P. Guidetti) (2004) 

 

10.  “Small Inhibitors of Kynurenine 3-Monooxygenase” (with P.J. Muchowski, J.M. Muchowski and P. Guidetti) (2007) U.S. Patent 7,994,338 (issued August 9, 2011)

 

11.  “Kynurenine Aminotransferase Inhibitors” (with Y. Kajii) (2007)

 

12.  “Inhibitors of Kynurenine Aminotransferase and Uses Therefor" (with P. Guidetti and R. Pellicciari) (2007)

 

13. “Small Molecule Inhibitors of Kynurenine 3-Monooxygenase” (with P.J. Muchowski and J.M. Muchowski) (2011) U.S. Patent 8,710,237 (issued April 29, 2014)

 

14. “A New Class of 3-Hydroxyanthranilate-3,4-dioxygenase (3-HAO) Inhibitors as Potential Neuroprotective Drugs” (with G. Costantino) (2011) United States Patent 9,260,394 (issued February 16, 2016)

 

15. "Derivatives of Nicotinic Acid N-Oxide, Their Preparation and Their Use as Inhibitors of Enzyme 3-Hydroxyanthranilate-3, 4-Dioxygenase" (with G. Costantino and L. Amori) (2015) United States Patent 9,487,486 (issued November 8, 2016)

 

Professional Activity

Editorial Boards, National and International Councils/Committees:

 

            "Neuropharmacology" (1987-1993)

            "Current CNS Patents" (1990-     )

            "Journal of Neural Transmission" (1996-2006)

           "Amino Acids" (1997-2009)

           “Current Drug Targets - CNS and Neurological Disorders” (1999-    )

           “Medicinal Chemistry Reviews” (2003-    )

           “Schizophrenia Bulletin” (2005-2010)

           “International Journal of Tryptophan Research” (2008-     )

           “Frontiers in Molecular Psychiatry” (2010-     )

            Scientific Council, Huntington's Disease Society of America (1987-1993)

            Council, International Study Group for Tryptophan Research (1987-1998)

            Member, Neurological Sciences 2, NINDS Study Section (1990-1994)

            Member, Investigator's Workshop Committee, American Epilepsy Society (1994-1997)       

            NIH Reviewer's Reserve (1994-1998)

            Scientific Advisory Committee, Huntington's Study Group for drug development (1994- 1998)

            Advisory Board, Vienna Brain Research Institute (Chair) (1995-2000)

            Member, Research Recognition Awards Committee, American Epilepsy Society (1999-2001)

            Member, Lennox Award Committee, American Epilepsy Society (1999-2001) (Chair, 2001)

            Member, ACNP Award Committee (2001)

            Member, ACNP Program Committee (2002-2004)

            Artemis Neuroscience, Inc., Scientific Advisory Board (Chair) (2002-2003)

             Vistagen, Inc., Scientific Advisory Board (2003-       )

             Member, Otto-Loewi-Preis Committee, Austrian Neuroscience Association (2005)

             Member, International Review Board, Vienna Brain Research Institute (2005-     )

             Member, ACNP Program Committee (2006-2008; Co-Chair, 2006, Chair, 2007)

             Member, Program Committee, American Epilepsy Society (2007-2008)

             Member, Research Initiative Fund Review Committee, American Epilepsy Society (2007-2009)

             Board of Trustees, MedicalUniversity of Vienna (2008-2018)

             Member, ACNP Liaison Committee with Government Agencies and the Pharmaceutical Industry (2009-2011)

             Member, Scientific Council, National Alliance for Research on Schizophrenia and Depression (NARSAD) (2009-     )

             Member, ACNP Ethics Committee (2012-2015)

             Member, ACNP Honorific Awards Committee (2016)