EFFECTS OF CALPAIN INHIBITION ON DOPAMINERGIC MARKERS AND MOTOR FUNCTION FOLLOWING INTRASTRIATAL 6-HYDROXYDOPAMINE ADMINISTRATION IN RATS
Identifieur interne : 002103 ( Main/Exploration ); précédent : 002102; suivant : 002104EFFECTS OF CALPAIN INHIBITION ON DOPAMINERGIC MARKERS AND MOTOR FUNCTION FOLLOWING INTRASTRIATAL 6-HYDROXYDOPAMINE ADMINISTRATION IN RATS
Auteurs : R. J. Grant [Canada] ; L. H. L. Sellings [Canada] ; S. J. Crocker [États-Unis] ; E. Melloni [Italie] ; D. S. Park [Canada] ; P. B. S. Clarke [Canada]Source :
- Neuroscience [ 0306-4522 ] ; 2009.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
The neurotoxin 6-hydroxydopamine has been widely used to model aspects of Parkinson's disease in rodents, but the mechanisms underlying toxin-induced dopaminergic degeneration and functional impairment have not been fully elucidated. The main aim of the present study was to assess a possible role for calpains in neurochemical and behavioral deficits following unilateral infusion of intrastriatal 6-hydroxydopamine in adult rats. Toxin administration produced a profound dopaminergic denervation, as indicated by a 90-95% reduction in dopamine transporter radiolabeling measured in the caudate-putamen at 2 weeks post-lesion. Treatment with 6-hydroxydopamine also resulted in calpain activation in both caudate-putamen and substantia nigra, as measured by the appearance of calpain-specific spectrin breakdown products. Calpain activation peaked at 24 h after 6-hydroxydopamine infusion and remained elevated at later time points. In contrast, caspase-3-mediated spectrin cleavage subsided within 48 h in both brain areas. In a subsequent experiment, calpain inhibition was achieved by intrastriatal infusion of an adenovirus expressing the endogenous calpain inhibitor, calpastatin. Calpastatin delivery abolished the lesion-induced calpain-mediated spectrin cleavage and alleviated forelimb asymmetries resulting from unilateral intrastriatal 6-hydroxydopamine. Unexpectedly, dopamine transporter and tyrosine hydroxylase labeling revealed significant neuroprotection, not in the nigrostriatal pathway but rather in the ventral tegmental area. These findings support a role for calpain activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. However, after near-total dopaminergic depletion, the primary benefit of calpain inhibition may not occur within the nigrostriatal dopaminergic pathway itself.
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">EFFECTS OF CALPAIN INHIBITION ON DOPAMINERGIC MARKERS AND MOTOR FUNCTION FOLLOWING INTRASTRIATAL 6-HYDROXYDOPAMINE ADMINISTRATION IN RATS</title><author><name sortKey="Grant, R J" sort="Grant, R J" uniqKey="Grant R" first="R. J." last="Grant">R. J. Grant</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325</s1><s2>Montreal, Quebec, H3G 1Y6</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec, H3G 1Y6</wicri:noRegion><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Sellings, L H L" sort="Sellings, L H L" uniqKey="Sellings L" first="L. H. L." last="Sellings">L. H. L. Sellings</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325</s1><s2>Montreal, Quebec, H3G 1Y6</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec, H3G 1Y6</wicri:noRegion><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Crocker, S J" sort="Crocker, S J" uniqKey="Crocker S" first="S. J." last="Crocker">S. J. Crocker</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue</s1><s2>Farmington, CT 06030</s2><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Farmington, CT 06030</wicri:noRegion></affiliation></author><author><name sortKey="Melloni, E" sort="Melloni, E" uniqKey="Melloni E" first="E." last="Melloni">E. Melloni</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Experimental Medicine, University of Genoa</s1><s2>16132 Genoa</s2><s3>ITA</s3><sZ>4 aut.</sZ></inist:fA14><country>Italie</country><wicri:noRegion>16132 Genoa</wicri:noRegion></affiliation></author><author><name sortKey="Park, D S" sort="Park, D S" uniqKey="Park D" first="D. S." last="Park">D. S. 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Clarke</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325</s1><s2>Montreal, Quebec, H3G 1Y6</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec, H3G 1Y6</wicri:noRegion><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">09-0119614</idno><date when="2009">2009</date><idno type="stanalyst">PASCAL 09-0119614 INIST</idno><idno type="RBID">Pascal:09-0119614</idno><idno type="wicri:Area/PascalFrancis/Corpus">000571</idno><idno type="wicri:Area/PascalFrancis/Curation">000721</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000473</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000473</idno><idno type="wicri:doubleKey">0306-4522:2009:Grant R:effects:of:calpain</idno><idno type="wicri:Area/Main/Merge">002277</idno><idno type="wicri:Area/Main/Curation">002103</idno><idno type="wicri:Area/Main/Exploration">002103</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">EFFECTS OF CALPAIN INHIBITION ON DOPAMINERGIC MARKERS AND MOTOR FUNCTION FOLLOWING INTRASTRIATAL 6-HYDROXYDOPAMINE ADMINISTRATION IN RATS</title><author><name sortKey="Grant, R J" sort="Grant, R J" uniqKey="Grant R" first="R. J." last="Grant">R. J. Grant</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325</s1><s2>Montreal, Quebec, H3G 1Y6</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec, H3G 1Y6</wicri:noRegion><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Sellings, L H L" sort="Sellings, L H L" uniqKey="Sellings L" first="L. H. L." last="Sellings">L. H. L. Sellings</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325</s1><s2>Montreal, Quebec, H3G 1Y6</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec, H3G 1Y6</wicri:noRegion><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Crocker, S J" sort="Crocker, S J" uniqKey="Crocker S" first="S. J." last="Crocker">S. J. Crocker</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue</s1><s2>Farmington, CT 06030</s2><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Farmington, CT 06030</wicri:noRegion></affiliation></author><author><name sortKey="Melloni, E" sort="Melloni, E" uniqKey="Melloni E" first="E." last="Melloni">E. Melloni</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Experimental Medicine, University of Genoa</s1><s2>16132 Genoa</s2><s3>ITA</s3><sZ>4 aut.</sZ></inist:fA14><country>Italie</country><wicri:noRegion>16132 Genoa</wicri:noRegion></affiliation></author><author><name sortKey="Park, D S" sort="Park, D S" uniqKey="Park D" first="D. S." last="Park">D. S. Park</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Neuroscience Research Group, Ottawa Health Research Institute, University of Ottawa</s1><s2>Ottawa, Ontario, K1H 8M5</s2><s3>CAN</s3><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, Ontario, K1H 8M5</wicri:noRegion></affiliation></author><author><name sortKey="Clarke, P B S" sort="Clarke, P B S" uniqKey="Clarke P" first="P. B. S." last="Clarke">P. B. S. Clarke</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325</s1><s2>Montreal, Quebec, H3G 1Y6</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec, H3G 1Y6</wicri:noRegion><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Neuroscience</title><title level="j" type="abbreviated">Neuroscience</title><idno type="ISSN">0306-4522</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Neuroscience</title><title level="j" type="abbreviated">Neuroscience</title><idno type="ISSN">0306-4522</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Calpain</term><term>Caspase</term><term>Corpus striatum</term><term>Dopamine</term><term>Oxidopamine</term><term>Rat</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Calpain</term><term>Dopamine</term><term>Oxidopamine</term><term>Caspase</term><term>Corps strié</term><term>Rat</term><term>Animal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The neurotoxin 6-hydroxydopamine has been widely used to model aspects of Parkinson's disease in rodents, but the mechanisms underlying toxin-induced dopaminergic degeneration and functional impairment have not been fully elucidated. The main aim of the present study was to assess a possible role for calpains in neurochemical and behavioral deficits following unilateral infusion of intrastriatal 6-hydroxydopamine in adult rats. Toxin administration produced a profound dopaminergic denervation, as indicated by a 90-95% reduction in dopamine transporter radiolabeling measured in the caudate-putamen at 2 weeks post-lesion. Treatment with 6-hydroxydopamine also resulted in calpain activation in both caudate-putamen and substantia nigra, as measured by the appearance of calpain-specific spectrin breakdown products. Calpain activation peaked at 24 h after 6-hydroxydopamine infusion and remained elevated at later time points. In contrast, caspase-3-mediated spectrin cleavage subsided within 48 h in both brain areas. In a subsequent experiment, calpain inhibition was achieved by intrastriatal infusion of an adenovirus expressing the endogenous calpain inhibitor, calpastatin. Calpastatin delivery abolished the lesion-induced calpain-mediated spectrin cleavage and alleviated forelimb asymmetries resulting from unilateral intrastriatal 6-hydroxydopamine. Unexpectedly, dopamine transporter and tyrosine hydroxylase labeling revealed significant neuroprotection, not in the nigrostriatal pathway but rather in the ventral tegmental area. These findings support a role for calpain activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. However, after near-total dopaminergic depletion, the primary benefit of calpain inhibition may not occur within the nigrostriatal dopaminergic pathway itself.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Italie</li><li>États-Unis</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Grant, R J" sort="Grant, R J" uniqKey="Grant R" first="R. J." last="Grant">R. J. Grant</name></region><name sortKey="Clarke, P B S" sort="Clarke, P B S" uniqKey="Clarke P" first="P. B. S." last="Clarke">P. B. S. Clarke</name><name sortKey="Park, D S" sort="Park, D S" uniqKey="Park D" first="D. S." last="Park">D. S. Park</name><name sortKey="Sellings, L H L" sort="Sellings, L H L" uniqKey="Sellings L" first="L. H. L." last="Sellings">L. H. L. Sellings</name></country><country name="États-Unis"><noRegion><name sortKey="Crocker, S J" sort="Crocker, S J" uniqKey="Crocker S" first="S. J." last="Crocker">S. J. Crocker</name></noRegion></country><country name="Italie"><noRegion><name sortKey="Melloni, E" sort="Melloni, E" uniqKey="Melloni E" first="E." last="Melloni">E. Melloni</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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