WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease
Identifieur interne : 000912 ( Main/Exploration ); précédent : 000911; suivant : 000913WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease
Auteurs : David A. Price [États-Unis] ; Alex A. Martinez [États-Unis] ; Alexandre Seillier [États-Unis] ; Wouter Koek [États-Unis] ; Yolanda Acosta [États-Unis] ; Elizabeth Fernandez [États-Unis] ; Randy Strong [États-Unis] ; Beat Lutz [Allemagne] ; Giovanni Marsicano [France] ; James L. Roberts [États-Unis] ; Andrea Giuffrida [États-Unis]Source :
- European Journal of Neuroscience [ 0953-816X ] ; 2009-06.
English descriptors
Abstract
Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.
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DOI: 10.1111/j.1460-9568.2009.06764.x
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Roberts</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Audie L. Murphy Veteran Affairs Medical Center, San Antonio, TX</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Giuffrida, Andrea" sort="Giuffrida, Andrea" uniqKey="Giuffrida A" first="Andrea" last="Giuffrida">Andrea Giuffrida</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Neuroscience</title><idno type="ISSN">0953-816X</idno><idno type="eISSN">1460-9568</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2009-06">2009-06</date><biblScope unit="volume">29</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2177">2177</biblScope><biblScope unit="page" to="2186">2186</biblScope></imprint><idno type="ISSN">0953-816X</idno></series><idno type="istex">28C8FFA08ABC3BA2D9EA00E5AE9C14069EDB31A8</idno><idno type="DOI">10.1111/j.1460-9568.2009.06764.x</idno><idno type="ArticleID">EJN6764</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0953-816X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>cannabinoid receptors</term><term>neuroinflammation</term><term>neurotoxicity</term><term>striatum</term><term>substantia nigra</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>États-Unis</li></country><region><li>Texas</li></region><settlement><li>Bordeaux</li></settlement></list><tree><country name="États-Unis"><region name="Texas"><name sortKey="Price, David A" sort="Price, David A" uniqKey="Price D" first="David A." last="Price">David A. Price</name></region><name sortKey="Acosta, Yolanda" sort="Acosta, Yolanda" uniqKey="Acosta Y" first="Yolanda" last="Acosta">Yolanda Acosta</name><name sortKey="Fernandez, Elizabeth" sort="Fernandez, Elizabeth" uniqKey="Fernandez E" first="Elizabeth" last="Fernandez">Elizabeth Fernandez</name><name sortKey="Fernandez, Elizabeth" sort="Fernandez, Elizabeth" uniqKey="Fernandez E" first="Elizabeth" last="Fernandez">Elizabeth Fernandez</name><name sortKey="Giuffrida, Andrea" sort="Giuffrida, Andrea" uniqKey="Giuffrida A" first="Andrea" last="Giuffrida">Andrea Giuffrida</name><name sortKey="Koek, Wouter" sort="Koek, Wouter" uniqKey="Koek W" first="Wouter" last="Koek">Wouter Koek</name><name sortKey="Koek, Wouter" sort="Koek, Wouter" uniqKey="Koek W" first="Wouter" last="Koek">Wouter Koek</name><name sortKey="Martinez, Alex A" sort="Martinez, Alex A" uniqKey="Martinez A" first="Alex A." last="Martinez">Alex A. Martinez</name><name sortKey="Roberts, James L" sort="Roberts, James L" uniqKey="Roberts J" first="James L." last="Roberts">James L. Roberts</name><name sortKey="Roberts, James L" sort="Roberts, James L" uniqKey="Roberts J" first="James L." last="Roberts">James L. Roberts</name><name sortKey="Seillier, Alexandre" sort="Seillier, Alexandre" uniqKey="Seillier A" first="Alexandre" last="Seillier">Alexandre Seillier</name><name sortKey="Strong, Randy" sort="Strong, Randy" uniqKey="Strong R" first="Randy" last="Strong">Randy Strong</name><name sortKey="Strong, Randy" sort="Strong, Randy" uniqKey="Strong R" first="Randy" last="Strong">Randy Strong</name></country><country name="Allemagne"><noRegion><name sortKey="Lutz, Beat" sort="Lutz, Beat" uniqKey="Lutz B" first="Beat" last="Lutz">Beat Lutz</name></noRegion></country><country name="France"><noRegion><name sortKey="Marsicano, Giovanni" sort="Marsicano, Giovanni" uniqKey="Marsicano G" first="Giovanni" last="Marsicano">Giovanni Marsicano</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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