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Mechanism-based approaches for the reversal of drug neurobehavioral teratogenicity

Joseph Yanai1, Tamar L Ben-Shaanan, Hana Haimovitch

  • 1The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Box 12272, 91010 Jerusalem, Israel. yanai@md.huji.ac.il

Annals of the New York Academy of Sciences
|November 16, 2006
PubMed

Insights

Neurobehavioral teratogenicity from drugs like heroin can be reversed. Nicotine infusion or neural progenitor grafting can correct hippocampus-related behavioral deficits caused by these toxins.

Area of Science:

  • Neuroscience
  • Developmental Neuroscience
  • Pharmacology

Background:

  • Neurobehavioral teratogenicity, resulting from prenatal exposure to toxins, presents significant challenges in understanding and treatment.
  • Hippocampus-dependent behaviors are particularly vulnerable to teratogenic insults, impacting cognitive development.
  • Identifying specific neurochemical pathways affected by teratogens is crucial for developing targeted interventions.

Purpose of the Study:

  • To elucidate the mechanism of neurobehavioral deficits induced by cholinergic teratogens, focusing on hippocampus-related behaviors.
  • To investigate the potential for reversing these teratogen-induced deficits using pharmacological and cellular therapies.
  • To establish a model for understanding and treating neurobehavioral birth defects.

Main Methods:

  • Utilized an animal model to study teratogen-induced deficits in eight-arm and Morris maze tasks, which are hippocampus-dependent.
  • Investigated the effects of cholinergic teratogens (e.g., heroin) on hippocampal cholinergic innervation and Protein Kinase C (PKC) signaling.
  • Evaluated the efficacy of nicotine infusion and neural progenitor grafting in reversing observed behavioral and molecular alterations.

Main Results:

  • Heroin exposure induced pre- and postsynaptic hyperactivity in hippocampal cholinergic innervation, leading to PKC isoform desensitization.
  • Nicotine infusion successfully reversed these teratogen-induced deficits and improved maze performance.
  • Grafting of embryonic cholinergic cells or neural progenitors also reversed biochemical alterations and behavioral deficits, with progenitor grafting showing higher efficacy.

Conclusions:

  • Understanding the specific neurochemical mechanisms of teratogenicity is key to developing effective reversal strategies.
  • Pharmacological interventions, such as nicotine infusion, offer a feasible and immediate therapeutic approach for neurobehavioral birth defects.
  • Neural progenitor grafting represents a promising, albeit more complex, treatment for reversing teratogen-induced neurodevelopmental abnormalities.

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