Developmental Brain Injury Proceedings and Abstracts of the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism Hershey, Pa., June 6–9, 2002 Guest Editors Susan J. Vannucci, New York, N.Y. Robert C. Vannucci, Hershey, Pa. Steven W. Levison, Hershey, Pa. 44 figures, 5 in color, and 7 tables, 2002 All papers have undergone the Journal’s usual peer review Basel(cid:1)Freiburg(cid:1)Paris(cid:1)London(cid:1)New York(cid:1) Bangalore(cid:1)Bangkok(cid:1)Singapore(cid:1)Tokyo (cid:1)Sydney S. Karger Drug Dosage All rights reserved. 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However, in view of ongoing research, changes microcopying, or by any information storage and retrieval Singapore (cid:1)Tokyo (cid:1)Sydney in government regulations, and the constant flow of informa- system, without permission in writing from the publisher or, in tion relating to drug therapy and drug reactions, the reader is the case of photocopying, direct payment of a specified fee to urged to check the package insert for each drug for any change the Copyright Clearance Center (see ‘General Information’). in indications and dosage and for added warnings and precau- tions. This is particularly important when the recommended © Copyright 2002 by S. Karger AG, agent is a new and/or infrequently employed drug. P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7572–6 Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com Vol. 24, No. 5, 2002 Contents 347 Preface Vannucci, S.J. (New York, N.Y.); Vannucci, R.C.; Levison, S.W. (Hershey, Pa.) Commentaries 349 Timing Is Everything – Delaying Therapy for Delayed Cell Death Ferriero, D.M. (San Francisco, Calif.) 352 New Approaches to Brain Injury in Preterm Infants Edwards, D. (London) Review 355 Under What Circumstances Can Seizures Produce Hippocampal Injury: Evidence for Age-Specific Effects Galanopoulou, A.S.; Vidaurre, J.; Moshé, S.L. (Bronx, N.Y.) Perspectives 364 Animal Models of Developmental Brain Injury: Relevance to Human Disease. A Summary of the Panel Discussion from the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism Hagberg, H. (Göteborg); Ichord, R. (Philadelphia, Pa.); Palmer, C. (Hershey, Pa.); Yager, J.Y. (Saskatoon); Vannucci, S.J. (New York, N.Y.) Original Papers 367 Prolonged Neonatal Seizures Exacerbate Hypoxic-Ischemic Brain Damage: Correlation with Cerebral Energy Metabolism and Excitatory Amino Acid Release Yager, J.Y.; Armstrong, E.A.; Miyashita, H. (Saskatoon); Wirrell, E.C. (Calgary) 382 Neuroprotection of Creatine Supplementation in Neonatal Rats with Transient Cerebral Hypoxia-Ischemia Adcock, K.H.; Nedelcu, J.† ; Loenneker, T.; Martin, E.; Wallimann, T. (Zurich); Wagner, B.P. (Berne) 389 Inhibition of nNOS and iNOS following Hypoxia-Ischaemia Improves Long-Term Outcome but Does Not Influence the Inflammatory Response in the Neonatal Rat Brain van denTweel, E.R.W.; Peeters-Scholte, C.M.P.C.D.; van Bel, F.; Heijnen, C.J.; Groenendaal, F. (Utrecht) © 2002 S. Karger AG, Basel Fax + 41 61 306 12 34 Access to full text and tables of contents, E-Mail [email protected] including tentative ones for forthcoming issues: www.karger.com www.karger.com/dne_issues 396 Effects of Selective Nitric Oxide Synthase Inhibition on IGF-1, Caspases and Cytokines in a Newborn Piglet Model of Perinatal Hypoxia-Ischaemia Peeters-Scholte, C.; Koster, J.; van den Tweel, E. (Utrecht); Blomgren, K. (Göteborg); Hamers, N. (Utrecht); Zhu, C. (Göteborg); van Buul-Offers, S. (Utrecht); Hagberg, H. (Göteborg); van Bel, F.; Heijnen, C.; Groenendaal, F. (Utrecht) 405 Evidence that p38 Mitogen-Activated Protein Kinase Contributes to Neonatal Hypoxic-Ischemic Brain Injury Hee Han, B. (Seoul/St. Louis, Mo.); Choi, J.; Holtzman, D.M. (St. Louis, Mo.) 411 Hypoxic Preconditioning Increases Brain Glycogen and Delays Energy Depletion from Hypoxia-Ischemia in the Immature Rat Brucklacher, R.M.; Vannucci, R.C. (Hershey, Pa.); Vannucci, S.J. (New York, N.Y.) 418 Early Appearance of Functional Deficits after Neonatal Excitotoxic and Hypoxic-Ischemic Injury: Fragile Recovery after Development and Role of the NMDA Receptor Felt, B.T. (Ann Arbor, Mich.); Schallert, T. (Ann Arbor, Mich./Austin, Tex.); Shao, J.; Liu, Y.; Li, X.; Barks, J.D.E. (Ann Arbor, Mich.) 426 Damage to the Choroid Plexus, Ependyma and Subependyma as a Consequence of Perinatal Hypoxia/Ischemia Rothstein, R.P.; Levison, S.W. (Hershey, Pa.) 437 IGF-I and NT-3 Signaling Pathways in Developing Oligodendrocytes: Differential Regulation and Activation of Receptors and the Downstream Effector Akt Ness, J.K.; Mitchell, N.E.; Wood, T.L. (Hershey, Pa.) 446 Abstracts 465 Author Index 466 Subject Index 346 Contents Dev Neurosci 2002;24:347–348 DOI: 10.1159/000069042 Preface SusanJ.Vannuccia RobertC.Vannuccib StevenW.Levisonb aDepartment of Pediatric Critical Care Medicine, Columbia University, New York, N.Y., and bDepartments of Pediatrics and Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Hershey, Pa., USA This special issue of Developmental Neuroscience rep- maturation and included talks by Mary McKenna, Uni- resents the proceedings of the Third Hershey Conference versity of Maryland; William J. Pearce, Loma Linda Uni- on Developmental Cerebral Blood Flow and Metabolism, versity; Steven W. Levison, Penn State University; Ray- which was held at the Hershey Hotel, Hershey, Pa., USA, mond Koehler, Johns Hopkins University, and Elly Ro- June 6–9, 2002. Drs. Susan and Robert Vannucci had cha, University of Western Ontario. organized this conference following two previously suc- The afternoon session of the first day focused on signal cessful conferences in June of 1997 and 2000. As in pre- transduction pathways as targets for cell preservation vious years, this year’s conference was an international after hypoxia/ischemia. Talks were presented by Donna meeting (with approximately 65 participants) that was Ferriero, University of California, San Francisco; Timo- highly interactive. Twenty-seven participants from 8 thy Schallert, University of Texas, Austin; David Holtz- countries, including the USA, presented plenary talks, man, Washington University School of Medicine; Henrik with 17 additional poster presentations. The conference Hagberg, Sahlgrenska University Hospital, Goteborg, brought together clinicians, basic scientists, fellows and Sweden; Tony Cheung, University of Hong Kong, Hong graduate students in a relaxed setting to share their dis- Kong, SAR China, and Christine Fox, University of Cali- coveries and thoughts with the goal of understanding the fornia, San Francisco. mechanisms that lead to perinatal brain injury and pro- The morning session of the second day was divided gress in identifying new treatments. The conference was into two sessions: the first focused on seizures, and the funded largely by the National Institute of Neurological second session focused on white matter damage. Seizures Disorders and Stroke (1R13 NS 43136) with an addition- are a frequent accompaniment to perinatal brain damage, al contribution from the Department of Pediatrics at Her- and so, they were a topic of several presentations. Talks shey. were presented by Harry Chugani, Wayne State Universi- Scientific sessions began with a keynote address by Dr. ty; Solomon Moshé, Albert Einstein College of Medicine, Richard Traystman, of Johns Hopkins University School and Jerome Yager, University of Saskatchewan, Canada. of Medicine. Dr. Traystman presented an enlightening, White matter damage is frequently observed in survivors entertaining, and provocative seminar on the cerebrovas- of perinatal hypoxic/ischemic brain damage and hence cular effects of cocaine in the fetus, newborn and adult. was the topic of several presentations. Talks on this sub- The next talks focused on the mechanisms of cerebral ject were presented by Terri Wood, Penn State College of ABC © 2002 S. Karger AG, Basel Susan J. Vannucci 0378–5866/02/0245–0347$18.50/0 Research Director, Pediatric Critical Care Medicine Fax +41 61 306 12 34 Morgan Stanley Children’s Hospital of New York/Columbia University E-Mail [email protected] Accessible online at: 3959 Broadway, BHN 10–24, New York, NY 10032 (USA) www.karger.com www.karger.com/dne Tel. +1 212 342 0275, Fax +1 212 342 2293, E-Mail [email protected] Medicine; Stephen A. Back, Oregon Health Sciences Uni- The final day of the meeting included a special talk by versity, and Stephen Miller, University of California, San Dr. Marvin Cornblath, who presented a historical per- Francisco. spective on newborn hypoglycemia. Following his talk, The afternoon session of the second day focused again the attendees participated in a panel discussion on animal on the mechanisms of hypoxic/ischemic brain damage. models of developmental brain injury. A synopsis of this Talks were presented by David Edwards, Imperial College discussion is provided in this special issue. of Medicine, Hammersmith Hospital, London, UK; Sid- At the end of the conference, there was complete agree- hartha Tan, Northwestern University; Cacha Peeters- ment that this had been yet another extremely exciting Scholte, University Medical Center, Wilhelmina Chil- and enlightening meeting, and it was unanimously de- dren’s Hospital, Utrecht, The Netherlands; Evelyn R. W. cided to schedule a fourth Conference on Developmental van den Tweel, University Medical Center, Wilhelmina Cerebral Blood Flow and Metabolism for June 2004. It Children’s Hospital, Utrecht, The Netherlands; Stéphane was further agreed that, although the conference will con- Sizonenko, University of Geneva, Geneva, Switzerland; tinue to be called the Hershey Conference, the location Courtney Robertson, University of Maryland School of will now alternate to include the West Coast, East Coast, Medicine; Ben Wagner, Unversity Children’s Hospital, and Europe. Donna Ferriero offered to host the next Berne Switzerland, and Andreas W. Loepke, University meeting, which will likely be in the Bay area of Califor- of Pennsylvania School of Medicine. nia. 348 Dev Neurosci 2002;24:347–348 Vannucci/Vannucci/Levison Commentary Dev Neurosci 2002;24:349–351 Received: August 22, 2002 Accepted: October 13, 2002 DOI: 10.1159/000069048 Timing Is Everything – Delaying Therapy for Delayed Cell Death DonnaM.Ferriero Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, Calif., USA Key Words newborn HI encephalopathy and stroke. This is in part Cell deathW TherapyW NeonateW Brain due to misguided assumptions that animal studies in the mature nervous system extrapolate to those of the neona- tal brain, and further assumptions that those data can be translated to clinical trials. In fact, that approach has Damage after a hypoxic-ischemic (HI) insult is both failed to produce a significant reduction of morbidity and region and cell population specific [Johnston, 1998]. This mortality from stroke in the adult, and certainly no thera- observation is critically evident in, and important to, the pies exist for HI or stroke in the newborn [Stroke Progress pathogenesis of the insult in the immature central nervous Review Group, 2002], even though a plethora of basic system. In the term human neonate, damage to the deep science contributions regarding the cell biology of the grey nuclei is seen using magnetic resonance imaging pathological processes exist [Dirnagl et al., 1999; Vexler (MRI) modalities such as diffusion tensor imaging, MR and Ferriero, 2001]. spectroscopy, and structural MRI [Barkovich et al., 1999, A potential reason for this failure is that the therapeu- 2001]. The loss of T -weighted signal in the posterior limb tic time window for treatment is thought to be limited to a 2 of the internal capsule has become the gold standard in few hours after the event. In point of fact, the tissue plas- predicting neurological injury with MRI [Rutherford et minogen activator trial for adult stroke excluded enroll- al., 1995]. Early spectroscopic changes of a variety of ment after 6 h, and the recent ‘head cooling’ trial for peri- metabolites like lactate, N-acetyl aspartate, choline and natal asphyxia did likewise [Gunn et al., 1998; Thoresen creatine using single-voxel techniques, coupled with the and Whitelaw, 2000]. However, if one critically examines presence of clinical neonatal seizures can aid in the accu- the existing cell biological data, especially for the develop- rate prediction of neurodevelopmental outcome after HI ing nervous system, it is clear that neuropathological in the term newborn [Miller et al., 2002]. Neonatal physi- changes evolve over weeks [Towfighi and Mauger, 1998], ological profiles in the first 24 h of life also contribute to a and that both the severity [Geddes et al., 2001] and age at better prediction of outcome in the mildly and severely the time of insult [Towfighi et al., 1997] dictate regional affected newborn [Newton et al., 2001]. vulnerability of brain structures. In both cortex and stria- Despite these advances in the recognition of injury and tum, there are at least biphasic stages of neurodegenera- prediction of neurodevelopmental outcome after HI, ther- tion after an HI insult in the neonatal rodent: early (1.5– apeutic advances are essentially nonexistent for the term 3h) and late (6 days!) [Northington et al., 2001]. ABC © 2002 S. Karger AG, Basel Donna M. Ferriero, MD 0378–5866/02/0245–0349$18.50/0 Departments of Neurology and Pediatrics, University of California San Francisco Fax +41 61 306 12 34 521 Parnassus Avenue C215 E-Mail [email protected] Accessible online at: San Francisco, CA 94143-0114 (USA) www.karger.com www.karger.com/dne Tel. +1 415 502 5820, Fax +1 415 502 5821, E-Mail [email protected] Fig. 1. Gene expression after ischemia. This cascade is documented for the mature rodent after focal ischemia, but is only presumed for the neonatal brain. Adapted from Ellison et al. [1999], copyright 1999, New York Academy of Sciences, USA. Careful anatomic studies demonstrate injury evolution activates the intermediate early genes (c-fos, c-jun, HSP) and ongoing cell death through 168 h [Nakajima et al., [Herdegen and Leah, 1998]. Simultaneously glutamate 2000] in rat cortex and striatum, as well as in mouse hip- receptors are activated by energy depletion and release of pocampus [Sheldon et al., 2001]. The nature of this cell presynaptic glutamate, triggering neuronal NOS activity death is complex, and has recently been termed the ‘apop- in vulnerable regions [Ferriero and Ashwal, 2002]. These totic-necrotic continuum’ by Martin et al. [Martin et al., injurious signals lead to intracellular oxidation of lipids, 1998]. Even in pure ischemia models in the neonatal proteins and nucleotides which results in structural dam- rodent, where blood flow is only transiently perturbed, age to mitochondria, endoplasmic reticulum, golgi, and injury evolves with a distinct time course and morphology plasma membranes. Selective cell death results in the [Manabat et al., 2000] in the core and penumbral regions availability of resistant killer (nNOS-containing) neurons of the infarct. partnered with invading microglia to stimulate inflamma- One proposal for future investigations is to treat early, tory processes and release more neurotoxins (OONO-, and treat again, using therapies (note plurality) to address cytokines, chemokines) that must be silenced in order for the cascade and time course of toxic events as they occur the vicious cycle to end [Beckman and Koppenol, 1996]. in the young brain (fig.1). When the existing literature Repair can then occur when growth factors, adhesion from studies mapping gene and protein expression after molecules and structural proteins and constituents, and neonatal HI is compiled, there are clear profiles that nurturing transcription factors like HIF1· are expressed emerge for a variety of cytotoxic and repair processes in regions of cell demise [Bergeron et al., 2000]. [Vexler and Ferriero, 2001; Ferriero, 2001]. Stress (HI) 350 Dev Neurosci 2002;24:349–351 Ferriero Therapy should be instituted ideally before the insult if cal advances can lead to promising areas of rescue in the we could be aware of impending doom (unfortunately promiscuous developing brain. Broadening the therapeut- babies do not have classical transient ischemic attacks). ic window, and designing age-appropriate therapies that However, there is a wide therapeutic window of opportu- address both cellular and regional selective vulnerability nity in the developing nervous system that would allow will eventually make perinatal HI encephalopathy, like for rescue of dying cells (both neurons and oligodendro- other neurological disorders, a treatable condition. cytes), even after the injury is complete. Stem cell biologi- References Barkovich AJ, Baranski K, Vigneron D, Partridge Geddes R, Vannucci RC, Vannucci SJ (2001): De- Northington FJ, Ferriero DM, Graham E, Trayst- JC, Hallam DK, Hajnal BL, Ferriero DM layed cerebral atrophy following moderate hyp- man RJ, Martin LJ (2001): Early neurodegen- (1999): Proton MR spectroscopy in the evalua- oxia-ischemia in the immature rat. 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