Amelioration of ischaemia-induced neuronal death in the rat striatum by NGF-secreting neural stem cells

Authors

  • Gunnar Andsberg,

    1. Section of Restorative Neurology, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden,
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  • Zaal Kokaia anders Björklund,

    1. Section of Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden,
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  • Olle Lindvall,

    1. Section of Restorative Neurology, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden,
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  • Alberto Martínez-Serrano

    1. Section of Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden,
    2. Center of Molecular Biology ‘Severo Ochoa’, Autonomous University of Madrid – CSIC, Campus Cantoblanco, Madrid, Spain
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Correspondence: Zaal Kokaia, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, S-221 85 Lund, Sweden. E-mail: zaza.kokaia@neurol.lu.se

Abstract

The objective of the present study was to explore whether grafted immortalized neural stem cells, genetically modified to secrete nerve growth factor (NGF), can ameliorate neuronal death in the adult rat striatum following transient middle cerebral artery occlusion (MCAO). One week after cell implantation in the striatum, animals were subjected to 30 min of MCAO. Striatal damage was evaluated at the cellular level after 48 h of recirculation using immunocytochemical and stereological techniques. The ischaemic insult caused an extensive degeneration of projection neurons, immunoreactive for dopamine- and adenosine 3′: 5′-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodaltons (DARPP-32). 3H-Thymidine autoradiography demonstrated surviving grafted cells in the lesioned striatum in all transplanted rats. The loss of striatal projection neurons was significantly reduced (by an average of 45%) in animals with NGF-secreting grafts, whereas control cells, not producing NGF, had no effect. The neuroprotective action of NGF-secreting grafts was also observed when the total number of striatal neurons immunopositive for the neuronal marker NeuN was quantified, as well as in cresyl violet-stained sections. The present findings indicate that administration of NGF by ex vivo gene transfer and grafting of neural stem cells can ameliorate death of striatal projection neurons caused by transient focal ischaemia.

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