Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats
Identifieur interne : 002D46 ( Main/Exploration ); précédent : 002D45; suivant : 002D47Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats
Auteurs : Kerry B. Goralski [Canada] ; Kenneth W. Renton [Canada]Source :
- Toxicology and applied pharmacology [ 0041-008X ] ; 2004.
Descripteurs français
- Pascal (Inist)
English descriptors
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Abstract
Experimental Parkinson's disease and Parkinson's disease in humans include a CNS inflammatory component that may contribute to the pathogenesis of the disease. CNS inflammation produces a loss in cytochrome P450 metabolism and may impair the brain's protection against neurotoxins. We have examined if preexisting inflammation in the brain could increase the toxicity of the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP+). Lipopolysaccharide (LPS, 25 μg) or saline (control) was injected into the left lateral cerebral ventricle. A single injection of MPP+ into the median forebrain bundle followed 48 h later and produced a reduction in striatal dopamine content that was dose and time dependant. Two-days after 5 μg of MPP+ was administered, a 90% decrease in striatal dopamine content was observed in saline- and LPS-pretreated rats. However, 4 and 7 days after 5 μg MPP+ treatment, striatal dopamine recovered up to 70-80% of control values in saline-pretreated rats but remained depressed (80-90%) in rats treated with LPS. These results suggested that CNS inflammation might create an increased risk factor for drug-induced CNS toxicity or chemically mediated Parkinson's disease. The prolonged toxicity of MPP+ may be due to a decrease in brain cytochrome P450 metabolism that occurs during inflammation. As a second objective for the study, we examined if the CNS lesion produced by MPP+ altered cytochrome P450 metabolic activity in the liver, kidney, and lung. We have demonstrated a novel mechanism whereby the brain pathology produced by MPP+ treatment contributes to a reduction in cytochrome P450 metabolism in the kidney but not the liver or lung. Therefore, a chemically evoked CNS disorder with a chronic inflammatory component might have major effects on the renal metabolism of drugs or endogenous substrates.
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats</title><author><name sortKey="Goralski, Kerry B" sort="Goralski, Kerry B" uniqKey="Goralski K" first="Kerry B." last="Goralski">Kerry B. Goralski</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacology, Dalhousie University</s1><s2>Halifax, Nova Scotia, B3H 1X5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Halifax, Nova Scotia, B3H 1X5</wicri:noRegion></affiliation></author><author><name sortKey="Renton, Kenneth W" sort="Renton, Kenneth W" uniqKey="Renton K" first="Kenneth W." last="Renton">Kenneth W. Renton</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacology, Dalhousie University</s1><s2>Halifax, Nova Scotia, B3H 1X5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Halifax, Nova Scotia, B3H 1X5</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">04-0457869</idno><date when="2004">2004</date><idno type="stanalyst">PASCAL 04-0457869 INIST</idno><idno type="RBID">Pascal:04-0457869</idno><idno type="wicri:Area/PascalFrancis/Corpus">000970</idno><idno type="wicri:Area/PascalFrancis/Curation">000353</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000895</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000895</idno><idno type="wicri:doubleKey">0041-008X:2004:Goralski K:brain:inflammation:enhances</idno><idno type="wicri:Area/Main/Merge">003117</idno><idno type="wicri:Area/Main/Curation">002D46</idno><idno type="wicri:Area/Main/Exploration">002D46</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats</title><author><name sortKey="Goralski, Kerry B" sort="Goralski, Kerry B" uniqKey="Goralski K" first="Kerry B." last="Goralski">Kerry B. Goralski</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacology, Dalhousie University</s1><s2>Halifax, Nova Scotia, B3H 1X5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Halifax, Nova Scotia, B3H 1X5</wicri:noRegion></affiliation></author><author><name sortKey="Renton, Kenneth W" sort="Renton, Kenneth W" uniqKey="Renton K" first="Kenneth W." last="Renton">Kenneth W. Renton</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacology, Dalhousie University</s1><s2>Halifax, Nova Scotia, B3H 1X5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Halifax, Nova Scotia, B3H 1X5</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Toxicology and applied pharmacology</title><title level="j" type="abbreviated">Toxicol. appl. pharmacol.</title><idno type="ISSN">0041-008X</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Toxicology and applied pharmacology</title><title level="j" type="abbreviated">Toxicol. appl. pharmacol.</title><idno type="ISSN">0041-008X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Basal ganglion</term><term>Cytochrome P450</term><term>Inflammation</term><term>Kidney</term><term>Lipopolysaccharide</term><term>Liver</term><term>Nervous system diseases</term><term>Parkinson disease</term><term>Rat</term><term>Toxicity</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Inflammation</term><term>Parkinson maladie</term><term>Toxicité</term><term>Système nerveux pathologie</term><term>Animal</term><term>Rat</term><term>Cytochrome P450</term><term>Lipopolyoside</term><term>Noyau gris central</term><term>Rein</term><term>Foie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Experimental Parkinson's disease and Parkinson's disease in humans include a CNS inflammatory component that may contribute to the pathogenesis of the disease. CNS inflammation produces a loss in cytochrome P450 metabolism and may impair the brain's protection against neurotoxins. We have examined if preexisting inflammation in the brain could increase the toxicity of the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>). Lipopolysaccharide (LPS, 25 μg) or saline (control) was injected into the left lateral cerebral ventricle. A single injection of MPP<sup>+</sup> into the median forebrain bundle followed 48 h later and produced a reduction in striatal dopamine content that was dose and time dependant. Two-days after 5 μg of MPP<sup>+</sup> was administered, a 90% decrease in striatal dopamine content was observed in saline- and LPS-pretreated rats. However, 4 and 7 days after 5 μg MPP<sup>+</sup> treatment, striatal dopamine recovered up to 70-80% of control values in saline-pretreated rats but remained depressed (80-90%) in rats treated with LPS. These results suggested that CNS inflammation might create an increased risk factor for drug-induced CNS toxicity or chemically mediated Parkinson's disease. The prolonged toxicity of MPP<sup>+</sup> may be due to a decrease in brain cytochrome P450 metabolism that occurs during inflammation. As a second objective for the study, we examined if the CNS lesion produced by MPP<sup>+</sup> altered cytochrome P450 metabolic activity in the liver, kidney, and lung. We have demonstrated a novel mechanism whereby the brain pathology produced by MPP<sup>+</sup> treatment contributes to a reduction in cytochrome P450 metabolism in the kidney but not the liver or lung. Therefore, a chemically evoked CNS disorder with a chronic inflammatory component might have major effects on the renal metabolism of drugs or endogenous substrates.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Goralski, Kerry B" sort="Goralski, Kerry B" uniqKey="Goralski K" first="Kerry B." last="Goralski">Kerry B. Goralski</name></noRegion><name sortKey="Renton, Kenneth W" sort="Renton, Kenneth W" uniqKey="Renton K" first="Kenneth W." last="Renton">Kenneth W. Renton</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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