Electroencephalographic Study of 137 Patients with Thalidomide Embryopathy

Kanno, Osamu

doi:10.1111/j.1440-1819.1987.tb00403.x

Cited by 5 publications

(14 citation statements)

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“…The most prominent teratogenic effect of THAL is phocomelia, but increasing evidence suggests that when taken at later stages, THAL causes a spectrum of neurological effects including autism and seizure disorders (Stephenson, 1976;Archer, 1978;Kanno, 1987;Stromland et al, 1994;Rodier et al, 1996). Since the only known mechanism of action of THAL implicated angiogenesis (D'Amato et al, 1994;Franks et al, 2004), the results presented here confirm that when given to pregnant rodents, THAL causes significant disturbances in brain cytoarchitecture and that this is due to altered development of CNS vasculature.…”

Section: Conclusion Thal As An Etiologic Factor For Neurological Dissupporting

confidence: 74%

“…That this increased incidence and prevalence of epilepsy is not a chance observation is supported by published clinical and experimental evidence of CNS abnormalities in THAL embryopathy, in addition to the known neurological effects of the drug in the adult (Stephenson, 1976;Kanno, 1987).…”

Section: Thal Epilepsy and Brain Developmentmentioning

confidence: 52%

“…When pregnant rats were exposed to THAL or VPA on embryonic day 9, a dramatic shift of the distribution of serotoninergic neurons in the dorsal raphe nucleus was observed postnatally. The relevance of this study is underscored by the fact that THAL exposure during human embryogenesis may lead to autism and epilepsy (Kanno, 1987;Stromland et al, 1994). How these data relate to what is shown in the present study remains to be fully elucidated.…”

Section: Thal Epilepsy and Brain Developmentmentioning

confidence: 63%

“…Furthermore, the angiogenesis inhibitor thalidomide (THAL) (Franks et al, 2004) causes brain malformations in humans and animal models (Narita et al, 2002;Teitelbaum, 2003;Miyazaki et al, 2005). Finally, prenatal exposure to THAL has been linked to adult or neonatal onset of seizures (Stephenson, 1976;Kanno, 1987).This prompted us to test the hypothesis that vascular development is an essential step in corticogenesis and that agents which interfere with this process may cause malformations of brain development. To assess this, we monitored cortical development of E15 SpragueDawley rats exposed to the angiogenesis inhibitor THAL.…”

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Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

et al. 2006

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Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. MCD are believed to be the morphological and perhaps physiological bases of several neurological diseases, spanning from mental retardation to autism and epilepsy. In view of the fact that during development, an appropriate blood supply is necessary to drive organogenesis in other organs, we hypothesized that vasculogenesis plays an important role in brain development and that E15 exposure in rats to the angiogenesis inhibitor thalidomide would cause postnatal MCD. Our results demonstrate that thalidomide inhibits angiogenesis in vitro at concentrations that result in significant morphological alterations in cortical and hippocampal regions of rats prenatally exposed to this vasculotoxin. Abnormal neuronal development was associated with vascular malformations and a leaky blood-brain barrier. Protein extravasation and uptake of fluorescent albumin by neurons, but not glia, was commonly associated with abnormal cortical development. Neuronal hyperexcitability was also a hallmark of these abnormal cortical regions. Our results suggest that prenatal vasculogenesis is required to support normal neuronal migration and maturation. Altering this process leads to failure of normal cerebrovascular development and may have a profound implication for CNS maturation.Keywords cortical dysplasia; angiogenesis; brain development; vasculogenesis; blood-brain barrier; endothelium Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. Genetic/epigenetically-induced MCD represent one of the most common etiologic factors associated with CNS pathologies, i.e. neurological deficits, autism, developmental delay, and epilepsy (Taylor et al., 1971;Robain, 1996). While the exact mechanisms underlying MCD are unknown, it is clear that single genes may be responsible for distinct MCD including lissencephaly, subcortical band heterotopias, NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2014 January 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript periventricular nodular heterotopia, and tuberous sclerosis (Gardiner, 1999;Steinlein, 2004). Although the exact pathogenesis of MCD remains unknown, environmental factors also appear to be involved (Montenegro et al., 2002;Montenegro, 2003;Bassanini and Battaglia, 2006).Animal models of CNS disorders have provided a crucial step toward both the understanding of mechanisms involved and discovery of therapeutic factors. In the case of MCD, the animal model that most realistically recapitulates the morphology of human cortical dysplasia is based on prenatal exposure to methylazoxymethanol acetate (MAM; Battaglia et al., 2003a). A prenatal exposure to this putative anti-proliferative and cytotoxic agent (Cattaneo et al., 1995) induces cerebral heterotopias that share striking similarities with those observed in humans (Colacitti et al., 1999;Battaglia et al., 2003a)...

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Section: Conclusion Thal As An Etiologic Factor For Neurological Dissupporting

confidence: 74%

Section: Thal Epilepsy and Brain Developmentmentioning

confidence: 52%

Section: Thal Epilepsy and Brain Developmentmentioning

confidence: 63%

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confidence: 99%

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confidence: 99%

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Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

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Thalidomide inhibits pentylenetetrazole-induced seizures

Palencia

Carreño

Sotelo

2007

Journal of the Neurological Sciences

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The Blood–Brain Barrier and Epilepsy

2006

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Summary:During the past several years, there has been increasing interest in the role of the blood-brain barrier (BBB) in epilepsy. Advances in neuroradiology have enhanced our ability to image and study the human cerebrovasculature, and further developments in the research of metabolic deficiencies linked to seizure disorders (e.g., GLUT1 deficiency), neuroinflammation, and multiple drug resistance to antiepileptic drugs (AEDs) have amplified the significance of the BBB's relationship to epilepsy.Prior to 1986, BBB research in epilepsy focused on three main areas: ultrastructural studies, brain glucose availability and transport, and clinical uses of AEDs. However, contrast-based imaging techniques and medical procedures such as BBB disruption provided a framework that demonstrated that the BBB could be reversibly disrupted by pathologic or iatrogenic manipulations, with important implications in terms of CNS drug delivery to "multiple drug resistant" brain. This concept of BBB breakdown for therapeutic purposes has also unveiled a previously unrecognized role for BBB failure as a possible etiologic mechanism in epileptogenesis. Finally, a growing body of evidence has shown that inflammatory mechanisms may participate in the pathological changes observed in epileptic brain, with increasing awareness that blood-borne cells or signals may participate in epileptogenesis by virtue of a leaky BBB. In this article we will review the relationships between BBB function and epilepsy. In particular, we will illustrate consensus and divergence between clinical reality and animal studies. Key Words: Antiepileptic drugs-Membrane transport proteins-Monosaccharide transport proteins-Epileptogenesis-Cerebral blood flow.Historically, the convergence between studies of bloodbrain barrier (BBB) and clinical investigation of the epilepsies has been limited to interactions between putative antiepileptic drugs (AED) and the endothelium (for a review of the original BBB studies in epilepsy see (Cornford and Oldendorf, 1986)). These studies were based on the observation that many promising antiepileptic drugs are excluded by the BBB and are thus clinically unusable in spite of significant potency and selectivity, as revealed by in vitro screening or animal models. More recently, it has become apparent that multiple drug resistance is only one of the aspects in BBB research that may impact how we define, prevent and treat seizure disorders. The following paragraphs will summarize recent findings and knowledge within a historical perspective of BBB relevance in the field of epilepsy research (see Fig. 1). Fig. 2 shows the proposed links between BBB and epilepsy. Drug resistance affecting approximately 30%

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Electroencephalographic Study of 137 Patients with Thalidomide Embryopathy

Cited by 5 publications

References 11 publications

Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

Thalidomide inhibits pentylenetetrazole-induced seizures

The Blood–Brain Barrier and Epilepsy

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