JOURNAL OF NEUROTRAUMA Volume 9, Number 2, 1992 Mary Ann Lieben, Inc., Publishers
Workshop on Experimental Spinal Cord Injury: Modeling and Criteria
NIH
Editors: DOUGLAS K.
ANDERSON, CHUNG
Y. HSU, MARY ELLEN and BRADFORD T. STOKES
MICHEL,
of the Journal ofNeurotrauma, which has come to serve as a vehicle for the of major status reports and state-of-the-art reviews, we are pleased to provide the following materials presented at a recent National Institutes of Health Workshop on Experimental Spinal Cord Injury. This workshop report has been organized and edited by Drs. Douglas Anderson, Chung Hsu, Mary Ellen Michel, and Bradford Stokes. The workshop presents a state-of-the-art review of spinal cord injury models, biologic variables, outcome measures, and criteria for preclinical trials. In this workshop report, each participant has provided a brief overview of his or her area of expertise related to spinal cord injury. The critical discussions that follow each presentation are included, together with brief synopses of the four major components of the workshop. The Editorial Board of the Journal has made no effort to reformat or rewrite this workshop report in the form of Journal articles. Rather, the reader is allowed to review the individual reports and to evaluate the critical discussion that follows. The Journal is pleased to have the opportunity to serve as the vehicle for this NIH Conference Workshop report. This report should prove of use to the seasoned investigator as well as the researcher first considering work in the field.
Continuing publication
in the tradition
CONTENTS
Participants Foreword. By MICHAEL D. WALKER Introduction. By MARY ELLEN MICHEL SESSION 1
SPINAL CORD INJURY MODELS
In Vitro Models of Mechanical
Injury. By JEN HILL LUCAS A Monitored Contusion Model of Spinal Cord Injury in the Rat. By JOHN A. GRÜNER Experimental Spinal Cord Injury: A Dynamic and Verifiable Injury Device. By BRADFORD T. STOKES
Commentary. By SESSION 2
Hemodynamic
DENNIS W. CHOI
BIOLOGIC VARIABLES Issues and Vascular Factors in Acute
Experimental Spinal
H. TATOR
Chemical and Cellular Mediators in
Spinal
Cord
Injury. By 113
Cord
Injury. By
DOUGLAS K. ANDERSON
CHARLES
NIH WORKSHOP ON EXPERIMENTAL SCI
Spinal Cord Injury
Models:
Neurophysiology. By
ANDREW R. BLIGHT
SESSION 3 OUTCOME MEASURES of Tissue
Rapid Quantification
Assessing Spinal Cord Injury Therapy. By WISE YOUNG After Spinal Cord Injury Produced by a Displacement Controlled
Damage
for
Anatomic and Behavioral Outcome Impact Device. By MICHAEL S. BEATTIE Problematic Issues in
Spinal
Cord
Injury. By
Using Experimental Models of Spinal Comment. By ALAN I. FADEN
SESSION 4
Cord
EDWARD L. HOGAN
Injury. By
JEAN R. WRATH ALL
CRITERIA FOR PRECLINICAL TRIALS
Importance of Pharmacologie Considerations in the Evaluation Cord Injury. By EDWARD D. HALL Criteria for Valid Preclinical Trials. By CHUNG Y. HSU Concluding Remarks. By WISE YOUNG
of New Treatments for Acute
Spinal
OUTLINE REPORT OF SPINAL CORD INJURY MODELS WORKSHOP PARTICIPANTS K. Anderson, Ph.D. Cincinnati VA Medical Center and Department of Neurology University of Cincinnati College of Medicine 231 Bethesda Avenue Cincinnati, OH 45267
Faden, M.D. Georgetown University Hospital Medical and Dental Building NW 103 Alan I.
Douglas
3900 Reservoir Road, N.W. Washington, DC 20007
John A. Grüner, Ph.D.
Beattie, Ph.D. Department of Anatomy Ohio State University
Department of Neurosurgery New York University Medical
Michael S.
1645 Neil Avenue
Columbus, Ohio 43210 Andrew R.
Center
550 First Avenue New York, New York 10016 Edward D. Hall, Ph.D. CNS Research The Upjohn Company Kalamazoo, Michigan 49001
Ph.D.
Blight, Department of Veterinary Anatomy Purdue University School of Veterinary Medicine Center for Paralysis Research West Lafayette, Indiana 47907 Dennis W. Choi, M.D., Ph.D. Department of Neurology Washington University School of Medicine
Edward L.
Hogan, M.D. Department Neurology Medical University of South 171 Ashley Avenue of
Carolina
Charleston, South Carolina 29425
660 S. Euclid Avenue St. Louis, Missouri 63110 114
NIH WORKSHOP ON EXPERIMENTAL SCI
Charles H.
Chung Y. Hsu, M.D., Ph.D. Department of Restorative Neurology & Human Neurobiology Baylor College of Medicine One Baylor Plaza
Tator, M.D., Ph.D. Department of Neurosurgery University of Toronto Toronto Western Hospital
Jen Hill Lucas, Ph.D.
Michael D. Walker, M.D. Division of Stroke and Trauma National Institute of Neurological Disorders and Stroke Federal Building, Room 800 Bethesda, Maryland 20892
399 Bathurst Street, Room EC2002 Toronto, Ontario, Canada M5T258
Houston, Texas 77030
Department of Physiology
404A Hamilton Hall Ohio State University 1645 Neil Avenue Columbus, Ohio 43210
Jean R. Wrathall, Ph.D.
Ellen Michel, Ph.D. Division of Stroke and Trauma National Institute of Neurological Disorders and Stroke Federal Building, Room 8A13 Bethesda, Maryland 20892
Mary
Department of Anatomy Georgetown University
and Cell
Biology
3900 Reservoir Road, N.W. Washington, DC 20007
Young, M.D., Ph.D. Department of Neurosurgery New York University Medical Wise
Bradford T. Stokes, Ph.D. Department of Physiology Ohio State University 1645 Neil Avenue Columbus, Ohio 43210
Center
550 First Avenue New York, New York 10016
FOREWORD 10 years of experience I had in a program that involved approximately 200 people in the National Cancer Institute in the drug development program. They started out with 50000 compounds during the heyday of the program and received potential drugs from all over the world. Companies seemed to pull compounds off their shelves. The program would process the latest hopeful drug through their stage one model system, which at that time happened to be the L-1210 tumor. It was a wonderful system with a predictable course reproducible in every sense of the word. The array of compounds went from 50000 to some 5000, which appeared to be effective in that system, and those could be refined in other systems down to 500. Those 500 then were moved into a series of other tumors, and from that refinement, they were able to get 50 compounds. They then set various scheduling approaches, and from that 50 were able to finally bring about 5 compounds to clinical trials. At the end of this period, a group of scientists sat down and said, "What have we learned from this? Are our model systems doing the job that we need, even though we identified drugs to test clinically? Are we missing promising leads?" So, someone took all the positive drugs and went back to the initial preclinical test and saw that, indeed, the L-1210 had picked them out. What about the other 499,000 candidate drugs that had been eliminated at the various stages along the way? Cisplatinum had flunked, yet this compound has one of the most extraordinary clinical effects of any drug that there is. A great many others had not been chosen for clinical testing. A very expensive operation was suddenly in question. We need to face these issues now, when we consider preclinical screening of drugs for spinal cord
I working continuously
wish to recount to you
injury. Screening of compounds is based on scientific investigation but is unique. From some people's point of view, you must study physiology. That is extremely important, but that is not the same as drug screening. From some points of view, you should study histology, and that is certainly important in providing guidelines, but that is not the same as drug screening. I think we must also think from a medical point of view, since, ultimately, we must justify our decisions to the American public. In that context, we need to discover something new. After many years and much expense in screening, we must have something that is going to be 115
NIH WORKSHOP ON EXPERIMENTAL SCI effective treatment. How do we select those drugs that will be most effective in spinal cord injury? When we come to the end of a drug-screening paradigm, will we have examined so many interesting compounds, both negative and positive, that we cannot bring anything to clinical trial? The minute we have a negative drug in clinical studies, we are inclined to abandon the screening system. But, really, it is then time to go back into that testing and find out why there was a false positive. Pick out the pieces—mechanisms, timing, dosing, biochemistry, physiology—so that new information is always gained. an
Michael D. Walker
INTRODUCTION OF the priorities for the Division of Stroke and Trauma and for the NINDS coming into the Decade of the Brain is clinical trials. We have had a positive clinical trial in spinal cord injury, and this presents the opportunity to do more clinically. There is a pipeline from basic science into clinical trials, and that is preclinical drug testing. We wish to obtain input from those investigators most active in spinal cord injury research to discuss the issues relevant to preclinical testing in their field: animal models and the variables inherent in them, selection of pharmacologie compounds, outcome measures, and protocol generation. We want to know how best to approach screening of compounds, so that future clinical trials are not delayed and are designed appropriately and resources are conserved. The focus of our workshop is preclinical drug screening. We recognize that not all models that provide excellent testing of scientific hypotheses are suited to this need. The two approaches complement and build on each other. Today, we talk critically about drug
One
development.
Mary Ellen Michel
116
Workshop on Experimental Spinal Cord Injury: Modeling and Criteria
NIH
Editors: DOUGLAS K.
ANDERSON, CHUNG
Y. HSU, MARY ELLEN and BRADFORD T. STOKES
MICHEL,
of the Journal ofNeurotrauma, which has come to serve as a vehicle for the of major status reports and state-of-the-art reviews, we are pleased to provide the following materials presented at a recent National Institutes of Health Workshop on Experimental Spinal Cord Injury. This workshop report has been organized and edited by Drs. Douglas Anderson, Chung Hsu, Mary Ellen Michel, and Bradford Stokes. The workshop presents a state-of-the-art review of spinal cord injury models, biologic variables, outcome measures, and criteria for preclinical trials. In this workshop report, each participant has provided a brief overview of his or her area of expertise related to spinal cord injury. The critical discussions that follow each presentation are included, together with brief synopses of the four major components of the workshop. The Editorial Board of the Journal has made no effort to reformat or rewrite this workshop report in the form of Journal articles. Rather, the reader is allowed to review the individual reports and to evaluate the critical discussion that follows. The Journal is pleased to have the opportunity to serve as the vehicle for this NIH Conference Workshop report. This report should prove of use to the seasoned investigator as well as the researcher first considering work in the field.
Continuing publication
in the tradition
CONTENTS
Participants Foreword. By MICHAEL D. WALKER Introduction. By MARY ELLEN MICHEL SESSION 1
SPINAL CORD INJURY MODELS
In Vitro Models of Mechanical
Injury. By JEN HILL LUCAS A Monitored Contusion Model of Spinal Cord Injury in the Rat. By JOHN A. GRÜNER Experimental Spinal Cord Injury: A Dynamic and Verifiable Injury Device. By BRADFORD T. STOKES
Commentary. By SESSION 2
Hemodynamic
DENNIS W. CHOI
BIOLOGIC VARIABLES Issues and Vascular Factors in Acute
Experimental Spinal
H. TATOR
Chemical and Cellular Mediators in
Spinal
Cord
Injury. By 113
Cord
Injury. By
DOUGLAS K. ANDERSON
CHARLES
NIH WORKSHOP ON EXPERIMENTAL SCI
Spinal Cord Injury
Models:
Neurophysiology. By
ANDREW R. BLIGHT
SESSION 3 OUTCOME MEASURES of Tissue
Rapid Quantification
Assessing Spinal Cord Injury Therapy. By WISE YOUNG After Spinal Cord Injury Produced by a Displacement Controlled
Damage
for
Anatomic and Behavioral Outcome Impact Device. By MICHAEL S. BEATTIE Problematic Issues in
Spinal
Cord
Injury. By
Using Experimental Models of Spinal Comment. By ALAN I. FADEN
SESSION 4
Cord
EDWARD L. HOGAN
Injury. By
JEAN R. WRATH ALL
CRITERIA FOR PRECLINICAL TRIALS
Importance of Pharmacologie Considerations in the Evaluation Cord Injury. By EDWARD D. HALL Criteria for Valid Preclinical Trials. By CHUNG Y. HSU Concluding Remarks. By WISE YOUNG
of New Treatments for Acute
Spinal
OUTLINE REPORT OF SPINAL CORD INJURY MODELS WORKSHOP PARTICIPANTS K. Anderson, Ph.D. Cincinnati VA Medical Center and Department of Neurology University of Cincinnati College of Medicine 231 Bethesda Avenue Cincinnati, OH 45267
Faden, M.D. Georgetown University Hospital Medical and Dental Building NW 103 Alan I.
Douglas
3900 Reservoir Road, N.W. Washington, DC 20007
John A. Grüner, Ph.D.
Beattie, Ph.D. Department of Anatomy Ohio State University
Department of Neurosurgery New York University Medical
Michael S.
1645 Neil Avenue
Columbus, Ohio 43210 Andrew R.
Center
550 First Avenue New York, New York 10016 Edward D. Hall, Ph.D. CNS Research The Upjohn Company Kalamazoo, Michigan 49001
Ph.D.
Blight, Department of Veterinary Anatomy Purdue University School of Veterinary Medicine Center for Paralysis Research West Lafayette, Indiana 47907 Dennis W. Choi, M.D., Ph.D. Department of Neurology Washington University School of Medicine
Edward L.
Hogan, M.D. Department Neurology Medical University of South 171 Ashley Avenue of
Carolina
Charleston, South Carolina 29425
660 S. Euclid Avenue St. Louis, Missouri 63110 114
NIH WORKSHOP ON EXPERIMENTAL SCI
Charles H.
Chung Y. Hsu, M.D., Ph.D. Department of Restorative Neurology & Human Neurobiology Baylor College of Medicine One Baylor Plaza
Tator, M.D., Ph.D. Department of Neurosurgery University of Toronto Toronto Western Hospital
Jen Hill Lucas, Ph.D.
Michael D. Walker, M.D. Division of Stroke and Trauma National Institute of Neurological Disorders and Stroke Federal Building, Room 800 Bethesda, Maryland 20892
399 Bathurst Street, Room EC2002 Toronto, Ontario, Canada M5T258
Houston, Texas 77030
Department of Physiology
404A Hamilton Hall Ohio State University 1645 Neil Avenue Columbus, Ohio 43210
Jean R. Wrathall, Ph.D.
Ellen Michel, Ph.D. Division of Stroke and Trauma National Institute of Neurological Disorders and Stroke Federal Building, Room 8A13 Bethesda, Maryland 20892
Mary
Department of Anatomy Georgetown University
and Cell
Biology
3900 Reservoir Road, N.W. Washington, DC 20007
Young, M.D., Ph.D. Department of Neurosurgery New York University Medical Wise
Bradford T. Stokes, Ph.D. Department of Physiology Ohio State University 1645 Neil Avenue Columbus, Ohio 43210
Center
550 First Avenue New York, New York 10016
FOREWORD 10 years of experience I had in a program that involved approximately 200 people in the National Cancer Institute in the drug development program. They started out with 50000 compounds during the heyday of the program and received potential drugs from all over the world. Companies seemed to pull compounds off their shelves. The program would process the latest hopeful drug through their stage one model system, which at that time happened to be the L-1210 tumor. It was a wonderful system with a predictable course reproducible in every sense of the word. The array of compounds went from 50000 to some 5000, which appeared to be effective in that system, and those could be refined in other systems down to 500. Those 500 then were moved into a series of other tumors, and from that refinement, they were able to get 50 compounds. They then set various scheduling approaches, and from that 50 were able to finally bring about 5 compounds to clinical trials. At the end of this period, a group of scientists sat down and said, "What have we learned from this? Are our model systems doing the job that we need, even though we identified drugs to test clinically? Are we missing promising leads?" So, someone took all the positive drugs and went back to the initial preclinical test and saw that, indeed, the L-1210 had picked them out. What about the other 499,000 candidate drugs that had been eliminated at the various stages along the way? Cisplatinum had flunked, yet this compound has one of the most extraordinary clinical effects of any drug that there is. A great many others had not been chosen for clinical testing. A very expensive operation was suddenly in question. We need to face these issues now, when we consider preclinical screening of drugs for spinal cord
I working continuously
wish to recount to you
injury. Screening of compounds is based on scientific investigation but is unique. From some people's point of view, you must study physiology. That is extremely important, but that is not the same as drug screening. From some points of view, you should study histology, and that is certainly important in providing guidelines, but that is not the same as drug screening. I think we must also think from a medical point of view, since, ultimately, we must justify our decisions to the American public. In that context, we need to discover something new. After many years and much expense in screening, we must have something that is going to be 115
NIH WORKSHOP ON EXPERIMENTAL SCI effective treatment. How do we select those drugs that will be most effective in spinal cord injury? When we come to the end of a drug-screening paradigm, will we have examined so many interesting compounds, both negative and positive, that we cannot bring anything to clinical trial? The minute we have a negative drug in clinical studies, we are inclined to abandon the screening system. But, really, it is then time to go back into that testing and find out why there was a false positive. Pick out the pieces—mechanisms, timing, dosing, biochemistry, physiology—so that new information is always gained. an
Michael D. Walker
INTRODUCTION OF the priorities for the Division of Stroke and Trauma and for the NINDS coming into the Decade of the Brain is clinical trials. We have had a positive clinical trial in spinal cord injury, and this presents the opportunity to do more clinically. There is a pipeline from basic science into clinical trials, and that is preclinical drug testing. We wish to obtain input from those investigators most active in spinal cord injury research to discuss the issues relevant to preclinical testing in their field: animal models and the variables inherent in them, selection of pharmacologie compounds, outcome measures, and protocol generation. We want to know how best to approach screening of compounds, so that future clinical trials are not delayed and are designed appropriately and resources are conserved. The focus of our workshop is preclinical drug screening. We recognize that not all models that provide excellent testing of scientific hypotheses are suited to this need. The two approaches complement and build on each other. Today, we talk critically about drug
One
development.
Mary Ellen Michel
116
