BDNF and TrkB in the Preterm and Near-term Ovine Fetal Brain and the Effect of Intermittent Umbilical Cord Occlusion

Abstract

We have determined the developmental change in immunoreactivity for brain-derived neurotrophic factor and its high-affinity tyrosine kinase receptor, TrkB, in the ovine fetal brain with advancing gestation and in response to intermittent umbilical cord occlusion, which might then contribute to adverse neurodevelopment. Fetal sheep (control and experimental groups at 0.75 and 0.90 of gestation) were studied over 4 days with umbilical cord occlusions performed in the experimental group animals by complete inflation of an occluder cuff for 90 seconds every 30 minutes for 3 to 5 hours each day. Animals were then euthanized and the fetal brains perfusion fixed and prepared for subsequent histology with the distribution of brain-derived neurotrophic factor and tyrosine kinase receptor immunoreactivity determined by immunohistochemistry. In the control group animals brain-derived neurotrophic factor immunoreactivity decreased in the gray matter, thalamus, and hippocampus but increased in the white matter, while tyrosine kinase receptor immunoreactivity decreased in all regions (most P < .01), with advancing gestation consistent with the developmental change from neurogenesis/gliagenesis to myelination over this time period. Intermittent umbilical cord occlusion as studied with severe but limited hypoxemia resulted in a variable decrease in brain-derived neurotrophic factor and tyrosine kinase receptor immunoreactivity for all brain regions in the preterm animals (most P < .01) when protein turnover is higher, but a selective increase in brain-derived neurotrophic factor immunoreactivity in the hippocampus of the near-term animals consistent with a heightened vulnerability for necrotic/apoptotic injury at this time. As such, brain-derived neurotrophic factor—tyrosine kinase receptor in the ovine fetal brain may be altered with intermittent hypoxic insults over the latter part of pregnancy with potential for longer term neurologic consequences.

Keywords

Brain development growth factors hypoxia.

Get full access to this article

View all access options for this article.

References

Anyaegbunam A. , Brustman L. , Divon M. , Langer O. The significance of antepartum variable decelerations . Am J Obstet Gynecol. 1986;155:707-710.

Dawes GS , Lobb MO , Mandruzzato G. , Moulden M. , Redman CW , Wheeler T. Large fetal heart rate decelerations at term associated with changes in fetal heart rate variation. Am J Obstet Gynecol. 1993;168:105-111.

Hoskins IA , Frieden FJ , Young BK Variable decelerations in reactive nonstress tests with decreased amniotic fluid index predict fetal compromise. Am J Obstet Gynecol . 1991;165: 1094-1098.

Clapp J. , Lopez B. , Simonean S. Nuchal cord and neurodevelopmental performance at 1 year. J Soc Gynecol Invest. 1999;6: 268-272.

Nelson K. , Grether J. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol. 1998;179:507-513.

Rocha E. , Hammond R. , Richardson B. Necrotic cell injury in the preterm and near-term ovine fetal brain after intermittent umbilical cord occlusion. Am J Obstet Gynecol . 1994;191:488-496.

Falkowski A. , Hammond R. , Han V. , Richardson B. Apoptosis in the preterm and near-term ovine fetal brain and the effect of intermittent umbilical cord occlusion. Develop Brain Res. 2002;136:165-173.

Rocha E. , Totten S. , Hammond R. , Han V. , Richardson B. Structural proteins during brain development in the preterm and near-term ovine fetus and the effect of intermittent umbilical cord occlusion. Am J Obstet Gynecol. 2004;191:497-506.

Kaneko M. , White S. , Homan J. , Richardson B. Cerebral blood flow and metabolism in relation to elecrocortical activity with severe umbilical cord occlusion in the near-term ovine fetus. Am J Obstet Gynecol. 2003;188:961-972.

10.

McAllister AK Neurotrophins and neuronal differentiation in the central nervous system. Cell Mol Life Sci. 2001;58:1054-1060.

11.

Binder DK , Scharfman HE Brain-derived neurotrophic factor. Growth Factors. 2004;22:123-131.

12.

Han VKM , Hill DJ Growth factors in fetal growth. Textbook of Fetal Physiology In: Thornburn GD , Harding R , eds. Oxford: Oxford Medical Publications; 1994:48-69.

13.

Duncan JR , Cock ML , Harding R. , Rees SM Neurotrophin expression in the hippocampus and cerebellum is affected by chronic placental insufficiency in the late gestational ovine fetus. Develop Brain Res. 2004;153:243-250.

14.

Dieni S. , Rees S. BDNK and TrkB protein expression is altered in the fetal hippocampus but not cerebellum after chronic prenatal compromise. Exper Neurol . 2005;192:265-273.

15.

Burkhalter J. , Fiumelli H. , Allaman I. , Chatton JY , Martin JL Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons. J Neurosci . 2003;23: 8212-8220.

16.

McIntosh GH , Baghurst KI , Potter BJ , Hetzel BS Foetal brain development in the sheep. Neuropathol Appl Neurobiol. 1979;5:103-114.

17.

Green L. , Homan J. , White S. , Richardson BS Cardiovascular and metabolic responses to intermittent umbilical cord occlusion in the preterm ovine fetus. J. Soc Gynecol Invest. 1999;6:55-63.

18.

Kawagoe Y. , Green L. , White S. , Richardson B. Intermittent umbilical cord occlusion in the ovine fetus near term: effects of behavioral state activity. Am J Obstet Gynecol. 1999;181:1520-1529.

19.

Bell AW , Kennaugh JM , Battaglia FC , Makowski EL , Meschia G. Metabolic and circulatory studies of fetal sheep at midgestation. Am J Physiol. 1986;250:E538-E544.

20.

Das KP , Chao SL , White LD , et al. Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain. Neurosci. 2001;103:739-761.

21.

Du Y. , Fischer TZ , Lee LN , Lercher LD , Dreyfus CF Regionally specific effects of BDNF on oligodendrocytes. Dev Neurosci. 2003;25:116-126.

22.

Mori T. , Shimizu K. , Hayashi M. Differential expression patterns of TrkB ligands in the macaque monkey brain . NeuroReport. 2004;15:2507-2511.

23.

Mori T. , Takumi K. , Shimizu K. , Oishi T. , Hayashi M. Heterogeneity of the developmental patterns of neurotrophin protein levels among neocortical areas of macaque monkeys. Exp Brain Res . 2006;171:129-138.

24.

Czikk MJ , Sweeley JC , Homan JH , Milley JR , Richardson BS Cerebral leucine metabolism and regional protein synthesis in the near term ovine fetus: relationship to fetal behavioural state. Am J Physiol. 2003;284:R200-R207.

25.

Kokaia Z. , Bengzon J. , Metsis M. , Kokaia M. , Persson H. , Lindvall O. Coexpression of neurotrophins and their receptors in neurons of the central nervous system. Proc Natl Acad Sci USA. 1993 ;90:6711-6715.

26.

Miranda RC , Sohrabji F. , Toran-Allerand CD Neuronal colocalization of mRNAs for neurotrophins and their receptors in the developing central nervous system suggests a potential for autocrine interactions . Proc Natl Acad Sci USA. 1993;90:6439-6443.

27.

Walton M. , Connor B. , Lawlor P. , et al. Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res Rev. 1999;29:137-168.

28.

Dunlop DS , van Elden W. , Lijtha A. Protein degradation rates in regions of the central nervous system in vivo during development. Biochem J. 1978;170:637-642.

29.

Arai S. , Kinouchi H. , Akabane A. , et al. Induction of brain-derived neurotrophic factor (BDNF) and the receptor trk B mRNA following middle cerebral artery occlusion in rat. Neurosci Lett. 1996;211:57-60.

30.

Smith M. , Auer RN , Siesjo BK The destiny and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia. Ann Neuropathol. 1984;64:319-332.

31.

Mallard EC , Williams CE , Johnston BM , Gluckman PD Increased vulnerability to neuronal damage after umbilical cord occlusion in fetal sheep with advancing gestation. Am J Obstet Gynecol . 1994;170:206-214.