Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts

Steingart, Ruth A.; Abu-Roumi, Moussa; Newman, Morris; Silverman, William F.; Slotkin, Theodore A.; Yanai, Joseph

doi:10.1016/s0165-3806(00)00063-8

Cited by 55 publications

(70 citation statements)

References 37 publications

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“…Muscarinic manipulation implicated the muscarinic signaling cascade, involving G proteins, Ca 2 þ elevation and PKC, in the proliferation of neural precursors. 64 In our model, prenatal heroin exposure induced defects of the cholinergic innervation, 16,17,23,45 terminating in PKC inactivation, 16,21,41,46 thus serving as a possible explanation for prenatal heroin inhibition of endogenous neural precursors proliferation. It is possible that the muscarinic signaling cascade may be part of, and/ or play a synergistic role to, the cytokine system, whose role in neurogenesis has been suggested by other investigators.…”

Section: Discussionmentioning

confidence: 83%

“…It should be noted that similar significance levels were shown with a two-tailed t-test for all major findings. Sex differences were considered in the analysis and in agreement with earlier work with prenatal heroin treatment, 16,17 the initial analysis of variance did not identify any significant interaction between treatment and sex; accordingly results from males and females are presented together. Significance for all tests was assumed at the level P < 0.05.…”

Section: Specific Methodsmentioning

confidence: 79%

“…[16][17][18][19][20][21][39][40][41] Both of these behavioral tests are affected by the cholinergic septohippocampal projection. [42][43][44] On the biochemical/molecular level, prenatal heroin induced both pre-and postsynaptic hyperactivity in the hippocampal cholinergic innervation, 16,17,23,45 converging on a total abolishment of the specific cholinergic-induced activation of PKCg. 16,21,41,46 This appears to be a major mechanism of these behavioral defects.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, administration of heroin to pregnant mice induced deficits in hippocampus-related offspring behavior and concomitant cholinergic-related abolishment of protein kinase C (PKC) activation. [16][17][18][19][20][21] Consequently, in the present study we employed our previously established allographic mouse model for the reversal of neurobehavioral defects by transplantation of neural progenitors toward testing the present question. Consistent with our previous studies, genetically heterogeneous HS/Ibg mice 22 were made deficient in the hippocampus-related Morris maze behavior and in its supposed mechanism, PKC function, by exposing them to heroin transplacentally.…”

Section: Introductionmentioning

confidence: 99%

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Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg À1 heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P < 0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P < 0.006) and reversed the behavioral defects (P < 0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

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Section: Discussionmentioning

confidence: 83%

Section: Specific Methodsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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“…Despite the fact that neuroteratogens affect a variety of regions and innervations, making the ascertaining of the mechanism difficult, a typical finding is cognitive impairment related to specific regions: hippocampus-related behaviors in rodents and the analogous IMHV-related imprinting and their associated cholinergic inputs [16,30,31,43]. Pinpointing the synaptic components that are affected by the neuroteratogen may offset or reverse the defects.…”

Section: Introductionmentioning

confidence: 99%

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

Wormser

Izrael

Zee

et al. 2005

Neurotoxicology and Teratology

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Citation for published version (APA): Wormser, U., Izrael, M., Van der Zee, E. A., Brodsky, B., & Yanai, J. (2005). A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity. Neurotoxicology and Teratology, 27(1), 65-71. DOI: 10.101665-71. DOI: 10. /j.ntt.2004 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractThe chemical warfare blistering agent, sulfur mustard (SM), is a powerful mutagen and carcinogen. Due to its similarity to the related chemotherapy agents nitrogen mustard (mechlorethamine), it is expected to act as a developmental neurotoxicant. The present study was designed to establish a chick model for the mechanisms of SM on neurobehavioral teratogenicity, free of confounds related to mammalian maternal effects. Chicken eggs were injected with SM at a dose range of 0.0017-17.0 Ag/kg of egg, which is below the threshold for dysmorphology, on incubation days (ID) 2 and 7, and then tests were conducted posthatching. Exposure to SM elicited significant deficits in the intermedial part of the hyperstriatum ventrale (IMHV)-related imprinting behavior. Parallel decreases were found in the level of membrane PKCg in the IMHV, while eliciting no net change in cytosolic PKCg. The chick, thus, provides a suitable model for the rapid evaluation of SM behavioral teratogenicity and elucidation of the mechanisms underlying behavioral anomalies. The results obtained, using a model that controls for confounding maternal effects, may be replicated in the mammalian model and provide the groundwork for studies designed to offset or reverse the SM-induced neurobehavioral defects in both avian and mammals. D

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Cholinergic synaptic signaling mechanisms underlying behavioral teratogenicity: Effects of nicotine, chlorpyrifos, and heroin converge on protein kinase C translocation in the intermedial part of the hyperstriatum ventrale and on imprinting behavior in an avian model

Izrael

Zee

Slotkin

et al. 2004

J of Neuroscience Research

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Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts

Cited by 55 publications

References 37 publications

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity

Cholinergic synaptic signaling mechanisms underlying behavioral teratogenicity: Effects of nicotine, chlorpyrifos, and heroin converge on protein kinase C translocation in the intermedial part of the hyperstriatum ventrale and on imprinting behavior in an avian model

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