Mechanism‐Based Approaches for the Reversal of Drug Neurobehavioral Teratogenicity

Abstract

Understanding the mechanism of neurobehavioral teratogenicity is the primary prerequisite for reversal of the defect. Progress in such studies can be best achieved if the investigation focuses on behaviors related to a specific brain region and innervation. Our model focused on teratogen-induced deficits in hippocampus-related eight-arm and Morris maze behaviors. Different "cholinergic" teratogens, mainly heroin, induced both pre- and postsynaptic hyperactivity in the hippocampal cholinergic innervation that terminated in desensitization of Protein Kinase C (PKC) isoforms to cholinergic receptor stimulation. Understanding this mechanism enabled its reversal with a pharmacological therapy-nicotine infusion. Studies by others provided similar findings by targeting the deficits respective to the model investigated. Consistently, destruction of the A10-septal dopaminergic pathways that downregulate the septohippocampal cholinergic innervation ameliorated maze performance. Grafting of embryonic differentiated cholinergic cells or neural progenitors similarly reversed the biochemical/molecular alterations and the resulting deficits. Reversal therapies offer a model for the understanding of neurobehavioral teratogenicity and, clinically, offer a model for potential treatment of these deficits. Whereas neural progenitor grafting appears to be the most effective treatment, pharmacological reversal with nicotine infusion seems to possess the most feasible and immediate therapy for neurobehavioral birth defects produced by various teratogens, including drugs. This is true even though the effect of pharmacological therapies is diffuse, affecting multiple areas of the brain. "Everybody is talking about the weather but nobody does anything about it." (Mark Twain).

Protein kinase C is a target for diverse developmental neurotoxicants: Transcriptional responses to chlorpyrifos, diazinon, dieldrin and divalent nickel in PC12 cells

“…Several studies point to cell signaling cascades that transduce the actions of numerous neurotransmitters and hormones as likely points of crosstalk for the integration of diverse trophic signals toward common events in neurodifferentiation, notably the inputs converging on protein kinases such as PKA, PKC and tyrosine kinases (Aldridge et al, 2005b; Kapfhammer, 2004; Meyer et al, 2004, 2005; Nakagawara, 2001; Reuss and von Bohlen und Halbach, 2003; Slikker et al, 2005; Slotkin et al, 2003, 2008c, 2009; Slotkin and Seidler, 2007; Yanai et al, 2002, 2004, 2006). The proof of the importance of these pathways has been reinforced by demonstrating amelioration or reversal of neurotoxicant effects by agents that offset the actions at the level of PKA or PKC (Beer et al, 2005; Slotkin et al, 2007a; Steingart et al, 2000; Yanai et al, 2006). …”

Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by allographic transplantation of adult subventricular zone‐derived neural stem cells

“…Our approach to overcome this methodological obstacle is to focus on a “region‐specific behavior,” that is, a performance test that can be linked reliably to a specific brain region and neurochemical pathway within that region. The Morris water maze test is highly correlated with the integrity of septohippocampal cholinergic innervation (Morris et al,1982; Yanai et al,2006). Our previous studies have shown that this input controls behavioral performance through the translocation of protein kinase C (PKC) to the cell membrane, and, consequently, the ability of neuroteratogens (including chlorpyrifos) to elicit deficits in hippocampal cholinergic‐induced PKC translocation is obligatorily linked to the behavioral deficits (Steingart et al,2000; Yaniv et al,2004).…”

Isolated congenital tracheal stenosis in a preterm newborn

“…External factors seem to interfere with the normal development of the respiratory tract in patients with tracheal atresia or severe tracheal stenosis [6, 20], but to date no common environmental agents or drugs have been identified to be the underlying cause for tracheal atresia and its associated anomalies. Although opioids are known to be of teratogenic effect to central nervous structures [22], there is no evidence for opioids to be involved in the determination of tracheal malformations. Since it is unknown, whether the mother of the reported baby took any other drugs than polamidone during early pregnancy, a drug effect contributing to the observed malformations cannot be ruled out.…”