Medical ProgressBrain damage in preterm newborns: Biological response modification as a strategy to reduce disabilities☆,☆☆
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)
- et al.
Long-term behavioral sequelae of prematurity
J Am Acad Child Adolesc Psychiatry
(1996) - et al.
Outcomes of children of extremely low birthweight and gestational age in the 1990’s
Early Hum Dev
(1999) - et al.
Ureaplasma urealyticum infection of the placenta in pregnancies that ended prematurely
Obstet Gynecol
(1996) - et al.
Bacterial vaginosis and intraamniotic infection
Am J Obstet Gynecol
(1997) - et al.
A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition
Am J Obstet Gynecol
(1998) - et al.
Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia
Am J Obstet Gynecol
(1996) - et al.
Recombinant human tumor necrosis factor alpha constricts pial arterioles and increases blood-brain barrier permeability in newborn piglets
Neurosci Lett
(1992) - et al.
Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia
Pediatr Neurol
(1996) - et al.
Characteristic neuropathology of leukomalacia in extremely low birth weight infants
Pediatr Neurol
(1997) - et al.
High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia
Am J Obstet Gynecol
(1997)
Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant
Semin Pediatr Neurol
Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits
Am J Obstet Gynecol
Endotoxin leucoencephalopathy in the telencephalon of the newborn kitten
J Neurol Sci
Cytokines and perinatal brain injury
Neurochem Int
Hypoxic-ischemic brain injury in the newborn. Cellular mechanisms and potential strategies for neuroprotection
Clin Perinatol
Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis
Neuron
Endogenous interleukin-1 receptor antagonist is neuroprotective
Biochem Biophys Res Commun
Kainic acid induced expression of interleukin-1 receptor antagonist mRNA in the rat brain
Brain Res Mol Brain Res
Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury
Brain Res
Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat
Exp Neurol
Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice
Brain Res
Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice
Brain Res Mol Brain Res
The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion
J Neuroimmunol
TNF alpha and IL-1beta mediate intercellular adhesion molecule-1 induction via microglia-astrocyte interaction in CNS radiation injury
J Neuroimmunol
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
P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat
Neurol Sci
Anti-P-selectin antibody attenuates rat brain ischemic injury
Neurosci Lett
IL-10 reduces rat brain injury following focal stroke
Neurosci Lett
Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis
Clin Ther
Rationale for early treatment with interferon beta-1a in relapsing-remitting multiple sclerosis
Clin Ther
Cell adhesion molecules in neural plasticity and pathology: Similar mechanisms, distinct organizations?
Prog Neurobiol
Outcome among surviving very low birthweight infants: a meta-analysis
Arch Dis Child
Changing prognosis for babies of less than 28 weeks’ gestation in the north of England between 1983 and 1994
BMJ
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
Results at age 8 years of early intervention for low-birth-weight premature infants. The Infant Health and Development Program
JAMA
The role of perinatal brain damage in developmental disabilities: an epidemiologic perspective
Ment Retard Dev Disabil Res Rev
Neonatal cranial ultrasound abnormalities in low birth weight infants: relation to cognitive outcomes at six years of age
Pediatrics
Cited by (55)
Pathophysiology
2018, Volpe's Neurology of the NewbornRole of Perinatal Inflammation in Cerebral Palsy
2009, Pediatric NeurologyCitation 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.
Quantitative DTI assessment of periventricular white matter changes in neonatal meningitis
2008, Brain and DevelopmentPerinatal Infections and Cerebral Palsy
2006, Clinics in Perinatology
- ☆
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.