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European Journal of Pediatrics 05/2012; 171(2):405-405. · 1.88 Impact Factor
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European Journal of Pediatrics 02/2012; 171(2):405; author reply 407. · 1.88 Impact Factor
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ABSTRACT: Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism. Here we examined, using microdialysis, the effect of thimerosal on extracellular levels of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal administration (4 injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino acid overflow: an increase of glutamate and aspartate accompanied by a decrease of glycine and alanine; measured 10-14 weeks after the injections. Four injections of thimerosal at a dose of 12.5 μg Hg/kg did not alter glutamate and aspartate concentrations at microdialysis time (but based on thimerosal pharmacokinetics, could have been effective soon after its injection). Application of thimerosal to the PFC in perfusion fluid evoked a rapid increase of glutamate overflow. Coadministration of the neurosteroid, dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate and aspartate; the steroid alone had no influence on these amino acids. Coapplication of DHEAS with thimerosal in perfusion fluid also blocked the acute action of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat potentiating the thimerosal effect on these amino acids. Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may partially protect against mercurials-induced neurotoxicity.
Neurochemical Research 02/2012; 37(2):436-47. · 2.24 Impact Factor
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ABSTRACT: The neurotoxic organomercurial thimerosal (THIM), used for decades as vaccine preservative, is a suspected factor in the pathogenesis of some neurodevelopmental disorders. Previously we showed that neonatal administration of THIM at doses equivalent to those used in infant vaccines or higher, causes lasting alterations in the brain opioid system in rats. Here we investigated neonatal treatment with THIM (at doses 12, 240, 1440 and 3000 μg Hg/kg) on behaviors, which are characteristically altered in autism, such as locomotor activity, anxiety, social interactions, spatial learning, and on the brain dopaminergic system in Wistar rats of both sexes. Adult male and female rats, which were exposed to the entire range of THIM doses during the early postnatal life, manifested impairments of locomotor activity and increased anxiety/neophobia in the open field test. In animals of both sexes treated with the highest THIM dose, the frequency of prosocial interactions was reduced, while the frequency of asocial/antisocial interactions was increased in males, but decreased in females. Neonatal THIM treatment did not significantly affect spatial learning and memory. THIM-exposed rats also manifested reduced haloperidol-induced catalepsy, accompanied by a marked decline in the density of striatal D₂ receptors, measured by immunohistochemical staining, suggesting alterations to the brain dopaminergic system. Males were more sensitive than females to some neurodisruptive/neurotoxic actions of THIM. These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute do neurodevelopmental disorders.
Behavioural brain research 09/2011; 223(1):107-18. · 3.22 Impact Factor
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ABSTRACT: Thimerosal added to some pediatric vaccines is suspected in pathogenesis of several neurodevelopmental disorders. Our previous study showed that thimerosal administered to suckling rats causes persistent, endogenous opioid-mediated hypoalgesia. Here we examined, using immunohistochemical staining technique, the density of μ-opioid receptors (MORs) in the brains of rats, which in the second postnatal week received four i.m. injections of thimerosal at doses 12, 240, 1,440 or 3,000 μg Hg/kg. The periaqueductal gray, caudate putamen and hippocampus were examined. Thimerosal administration caused dose-dependent statistically significant increase in MOR densities in the periaqueductal gray and caudate putamen, but decrease in the dentate gyrus, where it was accompanied by the presence of degenerating neurons and loss of synaptic vesicle marker (synaptophysin). These data document that exposure to thimerosal during early postnatal life produces lasting alterations in the densities of brain opioid receptors along with other neuropathological changes, which may disturb brain development.
Neurochemical Research 11/2010; 35(11):1840-7. · 2.24 Impact Factor
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ABSTRACT: Thimerosal (THIM), an organomercury preservative added to many child vaccines is a suspected factor in pathogenesis of neurodevelopmental disorders. We examined the pharmacokinetics of Hg in the brain, liver and kidneys after i.m. THIM injection in suckling rats and we tested THIM effect on nociception. THIM solutions were injected to Wistar and Lewis rats in a vaccination-like mode on PN days 7, 9, 11 and 15 in four equal doses. For Wistar rats these were: 12, 48, 240, 720, 1440, 2160, 3000 microg Hg/kg and for Lewis: 54, 216, 540 and 1080 microg Hg/kg. Pharmacokinetic analysis revealed that Hg from THIM injections accumulates in the rat brain in significant amounts and remains there longer than 30 days after the injection. At the 6th week of age animals were examined for pain sensitivity using the hot plate test. THIM treated rats of both strains and sexes manifested statistically significantly elevated pain threshold (latency for paw licking, jumping) on a hot plate (56 degrees C). Wistar rats were more sensitive to this effect than Lewis rats. Protracted THIM-induced hypoalgesia was reversed by naloxone (5 mg/kg, i.p.) injected before the hot plate test, indicative of involvement of endogenous opioids. This was confirmed by augmented catalepsy after morphine (2.5 mg/kg, s.c.) injection. Acute THIM injection to 6-week-old rats also produced hypoalgesia, but this effect was transient and was gone within 14 days. Present findings show that THIM administration to suckling or adult rats impairs sensitivity to pain, apparently due to activation the endogenous opioid system.
Brain research 09/2009; 1301:143-51. · 2.46 Impact Factor
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Maria Dorota Majewska
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ABSTRACT: Ion channels are vital components of plasma membranes. This article presents an evolutionary view of the biochemical mechanism of controlling activity of ion channels by rigid lipids, such as steroids or biophysically similar molecules, which were instrumental in formation and control of ion channels in cell membranes at the very origin of life. Such regulatory mechanisms exist in all cellular forms of life from ancient bacteria to humans and participate in a diversity of biological functions, from the most basic, such as maintenance of cell shape, homeostasis, feeding, cell fusion, and reproduction to the most intricate, such as the mind. Learning about the regulation of membrane ion channels by steroids and like molecules is important for understanding the evolution of life and various aspects of cell and organism physiology, for unraveling the mysteries of mind, and for practical purposes such as developing new pharmacotherapies.
Acta neurobiologiae experimentalis 02/2007; 67(3):219-33. · 2.11 Impact Factor
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ABSTRACT: Changes in plasma levels of cortisol and dehydroepiandrosterone sulfate (DHEA-S) following cocaine discontinuation were assessed in hospitalized chronic cocaine users. Measurements were performed after 6, 9, 18 and 21 days of abstinence. Repeated measures ANOVAs revealed significant time effects for cortisol (P<0.02) and DHEA-S (P<0.001). Changes in the two hormones did not follow the same course. Levels of cortisol were highest on day 6 and then subsequently decreased, whereas DHEA-S levels were low on day 6 and highest on day 18. Repeated measures ANCOVAs were used to test the overall effects of total duration of cocaine use, daily or weekly cocaine amounts consumed, or frequency of use on cortisol secretion. Analyses revealed a significant effect of frequency of use only (P<0.04). More sustained cocaine use was associated with higher cortisol levels and less pronounced cortisol decline after discontinuation of cocaine use, but drug intake variables had no influence on DHEA-S. The effects of presence or absence of life-long histories of aggression were also assessed. Repeated measures ANOVAs revealed a near significant group x time interaction for cortisol, which declined more dramatically in aggressive addicts than in non-aggressive addicts after day 6. DHEA-S was consistently higher in aggressive cocaine addicts, although this effect did not reach statistical significance. There was a noticeable difference in the dynamics of normalization of adrenal hormones between the two groups, with DHEA-S/cortisol ratios rising more dramatically during cocaine abstinence in aggressive than in non-aggressive addicts. In conclusion, lingering neuroendocrine perturbations persist after discontinuation of cocaine use in addicts. Some of these changes could be associated with an increased relapse risk.
Psychoneuroendocrinology 27(1-2):83-97. · 5.81 Impact Factor
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Maria Dorota Majewska
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ABSTRACT: Clinical and preclinical evidence links stress to drug dependence. Stress is accompanied by the rapid modification of brain and body physiology which leads to release of neuroactive hormones, including biogenic amines and adrenal steroids, which activate the same brain circuitry, as stimulant drugs, such as cocaine and amphetamines. Some preclinical studies showed that stress and elevated plasma concentrations of glucocorticoids increase acquisition and maintenance of stimulant use in rats, whereas other studies revealed that animals with inherently hypoactive HPA axis are more vulnerable to stimulant "abuse". In humans cocaine acutely activates the HPA axis, and in chronic cocaine abusers early abstinence is accompanied by alterations of the HPA axis function, with distinct patterns of hormonal changes characteristic for different subgroups of addicts. Some of these changes correspond to psychiatric comorbidities, which may be predictive of propensity to relapse. Hemispheric laterality plays a role in the stress-induced activation of the HPA axis, with right prefrontal cortex (PFC) having mostly stimulatory effects and the left, inhibitory effects. Brain-imaging studies showed preferential alteration of structure and function of the right cerebral hemisphere in cocaine addicts. Activation of the right PFC and inhibition of the left was noted in typical depressive disorders, and right hemispheric hypoactivity was reported in attention deficit hyperactivity and antisocial personality disorders, which are highly comorbid with stimulant dependence. Distinct patterns of hemispheric predominance or hypofunction between individuals may contribute to vulnerability or resilience to stimulant dependence. The nature and significance of the link between stress and activity of HPA axis, and vulnerability to drug dependence is not clear and deserves further study.
Psychoneuroendocrinology 27(1-2):5-12. · 5.81 Impact Factor
