A multitarget basal ganglia dopaminergic and GABAergic transplantation strategy enhances behavioural recovery in parkinsonian rats
Identifieur interne : 002250 ( Main/Exploration ); précédent : 002249; suivant : 002251A multitarget basal ganglia dopaminergic and GABAergic transplantation strategy enhances behavioural recovery in parkinsonian rats
Auteurs : K. Mukhida [Canada] ; M. Hong [Canada] ; G. B. Miles [Canada] ; T. Phillips [Canada] ; B. A. Baghbaderani [Canada] ; M. Mcleod [Canada] ; N. Kobayashi [Canada] ; A. Sen [Canada] ; L. A. Behie [Canada] ; R. M. Brownstone [Canada] ; I. Mendez [Canada]Source :
- Brain [ 0006-8950 ] ; 2008-08.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
The current transplantation paradigm for Parkinson's disease that places foetal dopaminergic cells in the striatum neither normalizes neuronal activity in basal ganglia structures such as the substantia nigra (SN) and subthalamic nucleus (STN) nor leads to complete functional recovery. It was hypothesized that restoration of parkinsonian deficits requires inhibition of the pathological overactivity of the STN and SN in addition to restoration of dopaminergic activity in the striatum. To achieve inhibition, a multitargeted basal ganglia transplantation strategy using GABAergic cells derived from either foetal striatal primordia (FSP) cells or human neural precursor cells (hNPCs) expanded in suspension bioreactors was investigated. In hemiparkinsonian rats, transplantation of foetal rat dopaminergic cells in the striatum in conjunction with GABAergic grafts in the STN and/or SN promoted significant improvement in forelimb akinesia and motor function compared to transplantation of intrastriatal dopaminergic grafts alone or in conjunction with undifferentiated hNPCs. In culture, FSP cells exhibited neuronal electrophysiological properties. However, recordings from GABAergic hNPCs revealed limited ionic conductances and an inability to fire action potentials. Despite this, they were almost as efficacious as FSP cells in inducing functional recovery following transplantation, suggesting that such recovery may have been mediated by secretion of GABA rather than by functional integration into the host. Thus, restoration of dopaminergic activity to the striatum in concert with inhibition of the STN and SN by GABAergic grafts may be beneficial for improving clinical outcomes in patients with Parkinson's disease and potential clinical application of this strategy may be enhanced by the use of differentiated hNPCs.
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DOI: 10.1093/brain/awn149
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Miles</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Cell Restoration Laboratory, Motor Control Laboratory, Departments of Anatomy & Neurobiology and Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada and Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, Calgary, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Phillips, T" sort="Phillips, T" uniqKey="Phillips T" first="T." last="Phillips">T. 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Baghbaderani</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Cell Restoration Laboratory, Motor Control Laboratory, Departments of Anatomy & Neurobiology and Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada and Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, Calgary, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Mcleod, M" sort="Mcleod, M" uniqKey="Mcleod M" first="M." last="Mcleod">M. 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Brownstone</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Cell Restoration Laboratory, Motor Control Laboratory, Departments of Anatomy & Neurobiology and Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada and Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, Calgary, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Mendez, I" sort="Mendez, I" uniqKey="Mendez I" first="I." last="Mendez">I. Mendez</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Cell Restoration Laboratory, Motor Control Laboratory, Departments of Anatomy & Neurobiology and Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada and Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, Calgary, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Canada</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-08">2008-08</date><biblScope unit="volume">131</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="2106">2106</biblScope><biblScope unit="page" to="2126">2126</biblScope></imprint><idno type="ISSN">0006-8950</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Basal ganglion</term><term>GABA</term><term>Nervous system diseases</term><term>Parkinson disease</term><term>Rat</term><term>Recovery</term><term>Strategy</term><term>Subthalamic nucleus</term><term>Transplantation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animal</term><term>GABA</term><term>Maladie de Parkinson</term><term>Noyau gris central</term><term>Noyau sousthalamique</term><term>Pathologie du système nerveux</term><term>Rat</term><term>Récupération</term><term>Stratégie</term><term>Transplantation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract">The current transplantation paradigm for Parkinson's disease that places foetal dopaminergic cells in the striatum neither normalizes neuronal activity in basal ganglia structures such as the substantia nigra (SN) and subthalamic nucleus (STN) nor leads to complete functional recovery. It was hypothesized that restoration of parkinsonian deficits requires inhibition of the pathological overactivity of the STN and SN in addition to restoration of dopaminergic activity in the striatum. To achieve inhibition, a multitargeted basal ganglia transplantation strategy using GABAergic cells derived from either foetal striatal primordia (FSP) cells or human neural precursor cells (hNPCs) expanded in suspension bioreactors was investigated. In hemiparkinsonian rats, transplantation of foetal rat dopaminergic cells in the striatum in conjunction with GABAergic grafts in the STN and/or SN promoted significant improvement in forelimb akinesia and motor function compared to transplantation of intrastriatal dopaminergic grafts alone or in conjunction with undifferentiated hNPCs. In culture, FSP cells exhibited neuronal electrophysiological properties. However, recordings from GABAergic hNPCs revealed limited ionic conductances and an inability to fire action potentials. Despite this, they were almost as efficacious as FSP cells in inducing functional recovery following transplantation, suggesting that such recovery may have been mediated by secretion of GABA rather than by functional integration into the host. Thus, restoration of dopaminergic activity to the striatum in concert with inhibition of the STN and SN by GABAergic grafts may be beneficial for improving clinical outcomes in patients with Parkinson's disease and potential clinical application of this strategy may be enhanced by the use of differentiated hNPCs.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Mukhida, K" sort="Mukhida, K" uniqKey="Mukhida K" first="K." last="Mukhida">K. Mukhida</name></noRegion><name sortKey="Baghbaderani, B A" sort="Baghbaderani, B A" uniqKey="Baghbaderani B" first="B. A." last="Baghbaderani">B. A. Baghbaderani</name><name sortKey="Behie, L A" sort="Behie, L A" uniqKey="Behie L" first="L. A." last="Behie">L. A. Behie</name><name sortKey="Brownstone, R M" sort="Brownstone, R M" uniqKey="Brownstone R" first="R. M." last="Brownstone">R. M. Brownstone</name><name sortKey="Hong, M" sort="Hong, M" uniqKey="Hong M" first="M." last="Hong">M. Hong</name><name sortKey="Kobayashi, N" sort="Kobayashi, N" uniqKey="Kobayashi N" first="N." last="Kobayashi">N. Kobayashi</name><name sortKey="Mcleod, M" sort="Mcleod, M" uniqKey="Mcleod M" first="M." last="Mcleod">M. Mcleod</name><name sortKey="Mendez, I" sort="Mendez, I" uniqKey="Mendez I" first="I." last="Mendez">I. Mendez</name><name sortKey="Mendez, I" sort="Mendez, I" uniqKey="Mendez I" first="I." last="Mendez">I. Mendez</name><name sortKey="Miles, G B" sort="Miles, G B" uniqKey="Miles G" first="G. B." last="Miles">G. B. Miles</name><name sortKey="Phillips, T" sort="Phillips, T" uniqKey="Phillips T" first="T." last="Phillips">T. Phillips</name><name sortKey="Sen, A" sort="Sen, A" uniqKey="Sen A" first="A." last="Sen">A. Sen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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