Prenatal cigarette smoke exposure selectively alters protein kinase C and nitric oxide synthase expression within the neonatal rat brainstem

Hasan, Shabih U.; Simakajornboon, Narong; MacKinnon, Yolanda; Gozal, David

doi:10.1016/s0304-3940(01)01624-x

Cited by 25 publications

(17 citation statements)

References 17 publications

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“…Superimposed on the overall induction of AC, there were deficits in the responses to stimulants working through GPs or GP-coupled receptors, indicating loss of response to stimulants acting upstream from AC. Accordingly, this pattern is virtually identical to what we found for the affects of heroin on PKC (Steingart et al, 1998(Steingart et al, , 2000b, and it appears to be a common feature of apparently unrelated neuroteratogens (Buznikov et al, 2001;Hasan et al, 2001, PerroneBizzozero et al, 1998.…”

Section: Neurochemical Alterationssupporting

confidence: 88%

“…Since alteration of PKC was generalized to many disparate neuroteratogens (Chen et al, 1997;Hasan et al, 2001;Haykal-Coates et al, 1998;Hussain et al, 2000;Johnson and Prohaska, 2000 ;Perrone-Bizzozero et al, 1998) the alterations in cholinergic innervation are actually heterologous. PKC is a common end-point for multiple signalling pathways.…”

Section: Neurochemical Alterationsmentioning

confidence: 99%

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Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation

Yanai

Huleihel

Izrael

et al. 2003

Int. J. Neuropsychopharm.

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Opioid drugs act primarily on the opiate receptors; they also exert their effect on other innervations resulting in non-opioidergic behavioural deficits. Similarly, opioid neurobehavioural teratogenicity is attested in numerous behaviours and neural processes which hinder the research on the mechanisms involved. Therefore, in order to be able to ascertain the mechanism we have established an animal (mouse) model for the teratogenicity induced by opioid abuse, which focused on behaviours related to specific brain area and innervation. Diacetylmorphine (heroin) and not morphine was applied because heroin exerts a unique action, distinguished from that of morphine. Pregnant mice were exposed to heroin (10 mg/kg per day) and the offspring were tested for behavioural deficits and biochemical alterations related to the septohippocampal cholinergic innervation. Some studies employing the chick embryo were concomitantly added as a control for the confounding indirect variables. Prenatal exposure to heroin in mice induced global hyperactivation both pre- and post-synaptic along the septohippocampal cholinergic innervation, including basal protein kinase C (PKC) activity accompanied by a desensitization of PKC activity in response to cholinergic agonist. Functionally, the heroin-exposed offspring displayed deficits in hippocampus-related behaviours, suggesting deficits in the net output of the septohippocampal cholinergic innervation. Grafting of cholinergic cells to the impaired hippocampus reversed both pre- and post-synaptic hyperactivity, resensitized PKC activity, and restored the associated behaviours to normality. Consistently, correlation studies point to the relative importance of PKC to the behavioural deficits. The chick model, which dealt with imprinting related to a different brain region, confirmed that the effect of heroin is direct. Taken together with studies by others on the effect of prenatal exposure to opioids on the opioidergic innervation and with what is known on the opioid regulation of the cholinergic innervation, it appears that heroin exerts its neuroteratogenicity by inducing alterations in the opioidergic innervation, which by means of its regulatory action, attenuates the functional output of the cholinergic innervation. In our model, there was hyperactivity mostly of the post-synaptic components of the cholinergic innervation. However, the net cholinergic output is decreased because PKC is desensitized to the effect of the cholinergic agonist, and this is further evidenced by the extensive deficits in the related behaviours.

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Section: Neurochemical Alterationssupporting

confidence: 88%

Section: Neurochemical Alterationsmentioning

confidence: 99%

Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation

Yanai

Huleihel

Izrael

et al. 2003

Int. J. Neuropsychopharm.

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“…The mechanism of inactivation may be of importance in understanding why the nNOS protein is decreased in penile (Xie et al, 1997) and brain tissue (Hasan et al, 2001) after exposure of rats to smoke. The accelerated degradation of nNOS has been observed with several other metabolism-based NOS inhibitors, including -ornithine, and guanabenz (Nakatsuka et al, 1998;Noguchi et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Exposure of rats to cigarette smoke causes a decrease in nNOS activity and nNOS protein in penile tissue while leaving eNOS protein unchanged (Xie et al, 1997). A loss of nNOS protein in rat brainstem was observed after prenatal exposure to cigarette smoke (Hasan et al, 2001), although no loss of nNOS protein was found in adult rat lung (Wright et al, 1999). Thus, it appears that smoking can lead to a selective loss of NOS activity and protein depending on the conditions and tissues; however, the mechanism by which this activity and protein are lost is not known.…”

mentioning

confidence: 99%

Metabolism-Based Inactivation of Neuronal Nitric-Oxide Synthase by Components of Cigarette and Cigarette Smoke

Demady

Lowe²,

Everett³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. LArginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.

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“…[83][84][85][86] Decreased brainstem immunoreactivity to selected protein kinase C and neuronal nitric oxide synthase isoforms has been observed in rats exposed to cigarette smoke prenatally, another potential cause of impaired hypoxic responsiveness. 87 Smoking increases susceptibility to viral and bacterial infections and increases bacterial binding after passive coating of mucosal surfaces with smoke components, implicating interactions between smoking, cardiorespiratory control and immune status.…”

mentioning

confidence: 99%

Sudden infant death syndrome

Hunt

Hauck²

2006

Canadian Medical Association Journal

177

112

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Prenatal cigarette smoke exposure selectively alters protein kinase C and nitric oxide synthase expression within the neonatal rat brainstem

Cited by 25 publications

References 17 publications

Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation

Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation

Metabolism-Based Inactivation of Neuronal Nitric-Oxide Synthase by Components of Cigarette and Cigarette Smoke

Sudden infant death syndrome

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