Advertisement
Original article| Volume 21, ISSUE 4, P248-252, June 01, 1999

Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion

      Abstract

      We conducted a chronic preparation experiment involving near term fetal sheep to evaluate the contribution of umbilical cord occlusion to fetal brain injury. In experimental groups (n=11), complete cord occlusion for 3 min followed by 5 min release, repeated 5 times were performed at 3 days after initial surgery. Instrumental cases without cord occlusion (n=3) and uninstrumental twins (n=6) were also examined as controls. Multiple necrotic foci predominantly in the periventricular white matter were found in the fetal brains examined at 1–3 days after cord occlusion. To estimate the contribution of early axonal and glial reaction to brain injury the following immunohistochemical study was performed. In the lesions, coagulation necrosis, axonal swelling and microglial activation were demonstrated with amyloid precursor protein or ionized calcium binding adapter molecule 1 immunohistochemistry. The induction of tumor necrosis factor alpha and inducible nitric oxide synthase were also detected immunohistochemically in the microglia at 1 and 3 days after cord occlusion. In contrast, the reaction of glial fibrillary acidic protein positive astrocytes was faint at 1 day after occlusion, but the induction of cyclooxygenase-2 was observed. These findings suggest the glial reaction of cytokines and free radicals induced by fetal hypoxia may contribute to the occurrence of brain injury.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Sunshine P. Epidemiology of perinatal asphyxia. In: Stevenson DK, Sunshine P, editors. Fetal and neonatal brain injury. Mechanisms, management, and the risks of practice. New York: Oxford University Press, 1997:3–23

        • Iida K.
        • Takashima S.
        • Takeuchi Y.
        Etiologies and distribution of neonatal leukomalacia.
        Pediatr Neurol. 1992; 8: 205-209
        • Iida K.
        • Takashima S.
        • Takeuchi Y.
        • Ohno T.
        • Ueda K.
        Neuropathologic study of newborns with prenatal-onset leukomalacia.
        Pediatr Neurol. 1993; 9: 45-48
        • Larroche J.C.
        • Aubry M.C.
        • Narcy F.
        Intrauterine brain damage in nonimmune hydrops fetalis.
        Biol Neonate. 1992; 61: 273-280
        • Marumo G.
        • Kozuma S.
        • Ohyu J.
        • Hamai Y.
        • Machida Y.
        • Kobayashi K.
        • et al.
        Possible mechanisms involved in the development of brain damage by repeated umbilical cord occlusion (in Japanease).
        Shyusankigaku Shinpojiumu (Tokyo). 1998; 16: 37-41
        • Fellman V.
        • Raivio K.O.
        Reperfusion injury as the mechanism of brain damage after perinatal asphyxia.
        Pediatr Res. 1997; 41: 599-606
        • Merrill J.E.
        • Benveniste E.N.
        Cytokines in inflammatory brain lesions: helpful and harmful.
        Trends Neurosci. 1996; 19: 331-338
        • Vannucci R.C.
        • Perlman J.M.
        Intervention for perinatal hypoxic-ischemic encephalopathy.
        Pediatrics. 1997; 100: 1004-1014
        • Giusanni D.A.
        • Spencer J.A.D.
        • Moore P.J.
        • Bennet L.
        • Hanson M.A.
        Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep.
        J Physiol. 1993; 461: 456-462
        • Imai Y.
        • Ibata I.
        • Ito D.
        • Ohsawa K.
        • Kohsaka S.
        A novel gene iba-1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage.
        Biochem Biophys Res Commum. 1996; 224: 855-862
        • Mallard E.C.
        • Gunn A.J.
        • Williams C.E.
        • Johnston B.M.
        • Gluckman P.D.
        Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep.
        Am J Obstet Gynecol. 1992; 167: 1423-1430
        • Mallard E.C.
        • Williams C.E.
        • Gunn A.J.
        • Gunning M.I.
        • Gluckman P.D.
        Frequent episodes of brief ischemia sensitize the fetal sheep brain to neuronal loss and induce striatal injury.
        Pediatr Res. 1993; 33: 61-65
        • Mallard E.C.
        • Williams C.E.
        • Johnston B.M.
        • Gunning M.I.
        • Davis S.
        • Gluckmann P.D.
        Repeated episodes of umbilical cord occlusion in fetal sheep lead to preferential damage to the striatum and sensitize the heart to further insults.
        Pediatr Res. 1995; 37: 707-713
        • Clapp J.F.
        • Peress N.S.
        • Wesley M.
        • Mann L.I.
        Brain damage after intermittent partial cord occlusion in the chronically instrumented fetal lamb.
        Am J Obstet Gynecol. 1988; 159: 504-509
        • Arai Y.
        • Deguchi K.
        • Mizuguchi M.
        • Takashima S.
        Expression of β-amyloid precursor protein in axons of periventricular leukomalacia brains.
        Pediatr Neurol. 1995; 13: 161-163
        • Ito D.
        • Imai Y.
        • Ohsawa K.
        • Nakajima K.
        • Fukuuchi Y.
        • Kohsaka S.
        Microglia-specific localisation of a novel calcium binding protein, Iba-1.
        Brain Res Mol Brain Res. 1998; 57: 1-9
        • Deguchi K.
        • Mizuguchi M.
        • Takashima S.
        Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia.
        Pediatr Neurol. 1996; 14: 13-16
        • Uno H.
        • Mastuyama T.
        • Akita H.
        • Nishimura H.
        • Sugita M.
        Induction of tumor necrosis factor-a in the mouse hippocampus following transient forebrain ischemia.
        J Cereb Blood Flow Metab. 1997; 17: 491-499
        • Iadecola C.
        Bright and dark sides of nitric oxide in ischemic brain injury.
        Trends Neurosci. 1997; 20: 132-139
        • Samdani A.F.
        • Dawson T.M.
        • Dawson V.L.
        Nitric oxide synthase in models of focal ischemia.
        Stroke. 1997; 28: 1283-1288
        • Kaufmann W.E.
        • Andreasson K.I.
        • Isakson P.C.
        • Worley P.F.
        Cyclooxygenase and the central nervous system.
        Prostaglandins. 1997; 54: 601-624
        • O'Banion M.K.
        • Miller J.C.
        • Chang J.W.
        • Kaplan M.D.
        • Coleman P.D.
        Interleukin-1β induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murine astrocyte cultures.
        J Neurochem. 1996; 66: 2532-2540
        • Nogawa S.
        • Zhang F.
        • Ross M.E.
        • Iadecola C.
        Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage.
        J Neurosci. 1997; 17: 2746-2755