Medical Progress
Brain damage in preterm newborns: Biological response modification as a strategy to reduce disabilities,☆☆

https://doi.org/10.1016/S0022-3476(00)90004-0Get rights and content

Abstract

Substances that promote the growth and maturation of oligodendrocytes and their precursors might protect against white matter injury. We suggest that neuroprotection can also be provided by such modulators of fetal and neonatal inflammatory responses as antiinflammatory cytokines, cytokine-binding proteins, and cytokine-receptor blockers. We briefly describe inflammatory responses in the fetus and newborn and show how they might contribute to brain damage. We conclude with the possibility that so-called biological response modifiers, which are drugs that modulate these inflammatory responses, might reduce the risk of brain damage and disabilities.(J Pediatr 2000;136:433-8)

Section snippets

ADVERSITIES OF PREMATURITY

Why should very preterm newborns be at such increased risk for cerebral white matter damage? One explanation is that they are more likely than term infants to be exposed to adversity. Although much of the current thinking still centers around postnatal insults, part of this increased risk for adversity appears to be associated with phenomena leading to preterm delivery (eg, intrauterine infection11, 12). Another part of the preterm newborn’s increased risk appears to be the ability to mount a

EXAMPLES OF INFLAMMATORY RESPONSE MODIFICATION

Genetic polymorphisms in specific cytokine loci (eg, for TNF-α) are one example of endogenous modification of the inflammatory response.46 What follows are examples for response modifiers with the potential for exogenous administration.

DISABILITY PREVENTION: A NEW APPLICATION FOR BIOLOGICAL RESPONSE MODIFICATION?

No report of a clinical trial of inflammation modulators to reduce brain damage in the newborn human has been published yet, although the earliest mention of the term biological response modifiers appears to have been in the late 1980s.

Biological response modifiers (BRMs) are agents or approaches that modify the relationship between the tumor and host by modifying the host’s biological responses to tumor cells, with resultant therapeutic effects. BRMs include immunomodulators and components of

THE DOUBLE-EDGED SWORD

The old saying of “no effect without a side effect” is once more confirmed within the scenario of brain protection through biological response modification. Some (if not most) target molecules exhibit fragile equilibria of biological activity. Thus blocking their activity might also be harmful. For example, cellular adhesion molecule blockage reduces brain damage in experimental models (see above). On the other hand, intervention designers will have to consider that it might also block their

References (75)

  • O Dammann et al.

    Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant

    Semin Pediatr Neurol

    (1998)
  • BH Yoon et al.

    Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits

    Am J Obstet Gynecol

    (1997)
  • FH Gilles et al.

    Endotoxin leucoencephalopathy in the telencephalon of the newborn kitten

    J Neurol Sci

    (1976)
  • FS Silverstein et al.

    Cytokines and perinatal brain injury

    Neurochem Int

    (1997)
  • AJ du Plessis et al.

    Hypoxic-ischemic brain injury in the newborn. Cellular mechanisms and potential strategies for neuroprotection

    Clin Perinatol

    (1997)
  • B Cheng et al.

    Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis

    Neuron

    (1994)
  • SA Loddick et al.

    Endogenous interleukin-1 receptor antagonist is neuroprotective

    Biochem Biophys Res Commun

    (1997)
  • C Eriksson et al.

    Kainic acid induced expression of interleukin-1 receptor antagonist mRNA in the rat brain

    Brain Res Mol Brain Res

    (1998)
  • GY Yang et al.

    Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury

    Brain Res

    (1997)
  • JK Relton et al.

    Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat

    Exp Neurol

    (1996)
  • C Gong et al.

    Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice

    Brain Res

    (1998)
  • GY Yang et al.

    Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice

    Brain Res Mol Brain Res

    (1999)
  • D Stanimirovic et al.

    The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion

    J Neuroimmunol

    (1997)
  • S Kyrkanides et al.

    TNF alpha and IL-1beta mediate intercellular adhesion molecule-1 induction via microglia-astrocyte interaction in CNS radiation injury

    J Neuroimmunol

    (1999)
  • GY Yang et al.

    Expression of intercellular adhesion molecule 1 (ICAM-1) is reduced in permanent focal cerebral ischemic mouse brain using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist

    Brain Res Mol Brain Res

    (1999)
  • AV Goussev et al.

    P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat

    Neurol Sci

    (1998)
  • H Suzuki et al.

    Anti-P-selectin antibody attenuates rat brain ischemic injury

    Neurosci Lett

    (1999)
  • PA Spera et al.

    IL-10 reduces rat brain injury following focal stroke

    Neurosci Lett

    (1998)
  • MM. Goldenberg

    Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis

    Clin Ther

    (1999)
  • FER Munschauer et al.

    Rationale for early treatment with interferon beta-1a in relapsing-remitting multiple sclerosis

    Clin Ther

    (1997)
  • CW Cotman et al.

    Cell adhesion molecules in neural plasticity and pathology: Similar mechanisms, distinct organizations?

    Prog Neurobiol

    (1998)
  • GJ Escobar et al.

    Outcome among surviving very low birthweight infants: a meta-analysis

    Arch Dis Child

    (1991)
  • W Tin et al.

    Changing prognosis for babies of less than 28 weeks’ gestation in the north of England between 1983 and 1994

    BMJ

    (1997)
  • A Hall et al.

    School attainment, cognitive ability and motor function in a total Scottish very-low-birthweight population at eight years: a controlled study

    Dev Med Child Neurol

    (1995)
  • CM McCarton et al.

    Results at age 8 years of early intervention for low-birth-weight premature infants. The Infant Health and Development Program

    JAMA

    (1997)
  • O Dammann et al.

    The role of perinatal brain damage in developmental disabilities: an epidemiologic perspective

    Ment Retard Dev Disabil Res Rev

    (1997)
  • AH Whitaker et al.

    Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age

    Pediatrics

    (1996)
  • Cited by (55)

    • Pathophysiology

      2018, Volpe's Neurology of the Newborn
    • Role of Perinatal Inflammation in Cerebral Palsy

      2009, Pediatric Neurology
      Citation Excerpt :

      Interferon-β provides an interesting example of a cytokine that effectively controls multiple sclerosis. These therapeutic models raised hopes that well-targeted immunomodulatory agents might also reduce the extent of brain lesions in other inflammatory diseases, especially those affecting the CNS [31]. However, no clinical trials using specific inflammatory modulators aimed at limiting brain damage in human newborns have yet been realized.

    • Perinatal Infections and Cerebral Palsy

      2006, Clinics in Perinatology
    View all citing articles on Scopus

    Supported by United Cerebral Palsy Research and Educational Foundation (EH-003-98).

    ☆☆

    Reprint requests: Olaf Dammann, MD, Neuroepidemiology Unit, CA 505, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115.

    View full text