Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol

Stefania Bassanini, Kerri Hallene, Giorgio Battaglia, Adele Finardi, Stefano Santaguida, Marilyn Cipolla, Damir Janigro

Research output: Contribution to journalArticlepeer-review

Abstract

One of the most common causes of neurological disabilities are malformations of cortical development (MCD). A useful animal model of MCD consists of prenatal exposure to methylazoxymethanol (MAM), resulting in a postnatal phenotype characterized by cytological aberrations reminiscent of human MCD. Although postnatal effects of MAM are likely a consequence of prenatal events, little is known on how the developing brain reacts to MAM. General assumption is the effects of prenatally administered MAM are short lived (24 h) and neuroblast-specific. MAM persisted for several days after exposure in utero in both maternal serum and fetal brain, but at levels lower than predicted by a neurotoxic action. MAM levels and time course were consistent with a different mechanism of indirect neuronal toxicity. The most prominent acute effects of MAM were cortical swelling associated with mild cortical disorganization and neurodegeneration occurring in absence of massive neuronal cell death. Delayed or aborted vasculogenesis was demonstrated by MAM's ability to hinder vessel formation. In vitro, MAM reduced synthesis and release of VEGF by endothelial cells. Decreased expression of VEGF, AQP1, and lectin-B was consistent with a vascular target in prenatal brain. The effects of MAM on cerebral blood vessels persisted postnatally, as indicated by capillary hypodensity in heterotopic areas of adult rat brain. In conclusion, these results show that MAM does not act only as a neurotoxin per se, but may additionally cause a short-lived toxic effect secondary to cerebrovascular dysfunction, possibly due to a direct anti-angiogenic effect of MAM itself.

Original languageEnglish
Pages (from-to)481-495
Number of pages15
JournalNeurobiology of Disease
Volume26
Issue number2
DOIs
Publication statusPublished - May 2007

Keywords

  • Angiogenesis
  • Blood-brain barrier
  • Brain development
  • Malformations of cortical development
  • Prenatal toxicity
  • Vasculogenesis

ASJC Scopus subject areas

  • Neurology

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