α-Bungarotoxin blocks the nicotinic receptor mediated increase in cell number in a neuroendocrine cell line

Quik, Maryka; Chan, Jack; Patrick, Jim

doi:10.1016/0006-8993(94)91610-1

Cited by 87 publications

(48 citation statements)

References 20 publications

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“…As just one example, the significant reductions in chrna7, which encodes the α7 nAChR, is consistent with the targeting of this receptor subtype by developmental CPF exposure [95]. Although α7 nAChRs are sparse when compared to the more abundant α4β2 subtype, it is the α7 unit that is overexpressed during brain development [2,15,35,84,115] and is most clearly involved in neuritic outgrowth [19,78], neurotoxicity and neuroprotection [24,40,45,58,103,104]. In addition to the common effect on chrna7, CPF and DZN had substantially disparate actions on a large number of other nAChR genes, with much more widespread consequences for DZN.…”

Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 59%

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Slotkin

Seidler

2007

Brain Research Bulletin

190

208

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Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1 mg/kg) or diazinon (1 or 2 mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity.

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Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 59%

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Slotkin

Seidler

2007

Brain Research Bulletin

190

208

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“…Nevertheless, there were strong regional disparities in the response, with the greatest increase seen in the occipital cortex, less in the hippocampus, brainstem and frontal cortex, and least in the caudate, suggesting differential susceptibility to nicotine-induced cellular effects. That conclusion was reinforced first by the finding that only the occipital cortex showed upregulation of a7nAChRs, the receptor subpopulation specifically associated with responses to cell injury and neuritic development (Chan and Quik, 1993;Quik et al, 1994;Verbois et al, 2002), and this same region showed a deficit in the membrane/total protein ratio, a biomarker for neuronal projections. Nicotine also had an adverse effect on cell number, as indicated by a significant overall decrement in the DNA concentration.…”

Section: Discussionmentioning

confidence: 97%

“…The a4b2nAChR is the most abundant form in the mammalian brain (Flores et al, 1992;Happe et al, 1994;Whiting and Lindstrom, 1987;Whiting and Lindstrom, 1988) and its upregulation by nicotine in the fetus is mechanistically involved in the adverse effects of nicotine on cell development, as well as providing a biomarker for neural cell stimulation by nicotine (Levin and Slotkin, 1998;Slotkin, 1992Slotkin, , 1999Slotkin, , 2004. Although present in lower concentrations, the a7nAChR is closely associated with the response to brain injury (Verbois et al, 2002) and with the effects of nicotine on neuritic outgrowth (Chan and Quik, 1993;Quik et al, 1994). Second, we focused on the effects on neurotransmitter receptors and cell signaling proteins that control the generation of the second messenger, cyclic AMP.…”

Section: Introductionmentioning

confidence: 99%

Effects of Prenatal Nicotine Exposure on Primate Brain Development and Attempted Amelioration with Supplemental Choline or Vitamin C: Neurotransmitter Receptors, Cell Signaling and Cell Development Biomarkers in Fetal Brain Regions of Rhesus Monkeys

Slotkin

Seidler

Qiao

et al. 2004

Neuropsychopharmacol

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Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.

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“…Generally, f-adrenoceptors mediate the activation of adenylyl cyclase (Lefkowitz et al, 1983) and such an effect may also be involved in the present inhibition of 5-HT release from NEE cells. At least forskolin, which is known to activate directly adenylyl cyclase (Seamon et al, 1981) (Nylen et al, 1993) or in different neuroendocrine cell lines derived from small cell lung cancer (Schuler, 1989;Tarroni et al, 1992;Catteneo et al, 1993;Quik et al, 1994). Whether this discrepancy reflects species differences or cell specific differences (NEE of upper versus lower airways) remains to be established.…”

Section: Inhibitory P-adrenoceptors and Role Of Cyclic Ampmentioning

confidence: 99%

Adrenoceptor‐ and cholinoceptor‐mediated mechanisms in the regulation of 5‐hydroxytryptamine release from isolated tracheae of newborn rabbits

Freitag

Wessler

Racké

1996

British J Pharmacology

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1 Isolated tracheae of newborn rabbits were incubated in vitro and the outflow of 5-hydroxytryptamine (5-HT) was determined by h.p.l.c. with electrochemical detection. Evidence has previously been provided that this 5-HT outflow derives from neuroendocrine epithelial (NEE) cells of the airway mucosa. 4 5-HT outflow evoked by 10 IM phenylephrine was inhibited by 65% in the presence of 1 gM forskolin and abolished in the presence of 10 gM forskolin. 5 5-HT outflow evoked by 10 gM phenylephrine was inhibited by about 45 and 70% in the presence of 0.1 and 1 gM isoprenaline, respectively. The inhibitory effect of 1 gM isoprenaline was only marginally antagonized by 1 gM, but blocked by 10 gM propranolol.6 5-HT outflow was not affected by the muscarine receptor agonist oxotremorine (10 gM), but was enhanced by 175% by 100 gM nicotine. The effect of nicotine was blocked by 100 gM hexamethonium and prevented by 1 gM tetrodotoxin or 1 gM yohimbine. 7 In conclusion, 5-HT release from NEE cells of the rabbit trachea is stimulated via a-adrenoceptors most likely of the a2B-subtype localized directly at the NEE cells. Activation of ,B-adrenoceptors as well as direct activation of adenylyl cyclase by forskolin exert inhibitory effects on 5-HT release. Activation of nicotinic, but not of muscarinic receptors, also evokes the release of 5-HT. However, the effect of nicotine appears to be mediated indirectly via the release of noradrenaline.

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α-Bungarotoxin blocks the nicotinic receptor mediated increase in cell number in a neuroendocrine cell line

Cited by 87 publications

References 20 publications

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Effects of Prenatal Nicotine Exposure on Primate Brain Development and Attempted Amelioration with Supplemental Choline or Vitamin C: Neurotransmitter Receptors, Cell Signaling and Cell Development Biomarkers in Fetal Brain Regions of Rhesus Monkeys

Adrenoceptor‐ and cholinoceptor‐mediated mechanisms in the regulation of 5‐hydroxytryptamine release from isolated tracheae of newborn rabbits

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