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Combining Neuroprotective Treatment of Embryonic Nigral Donor Tissue With Mild Hypothermia of the Graft Recipient

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Abstract:

Around 80–95% of the immature dopaminergic neurons die when embryonic ventral mesencephalic tissue is transplanted. Cell death occurs both during the preparation of donor tissue and after graft implantation, but the effect of combining successful neuroprotective treatments before and after transplantation has not been extensively investigated. We therefore treated embryonic rat mesencephalic tissue with a combination of the lipid peroxidation inhibitor tirilazad mesylate (3 M) and the caspase inhibitor Ac.YVAD.cmk (500 M) and transplanted the tissue into hemiparkinsonian rats kept hypothermic (32–33°C) or normothermic (37°C) during, and 90 min following, graft surgery. Suspension cell number did not differ between untreated or tirilazad/YVAD-treated preparations prior to transplantation. When graft survival was evaluated 6 weeks after implantation, both tirilazad/YVAD pretreatment and mild hypothermia increased the survival of transplanted dopaminergic neurons. Approximately 50–57% of the embryonic dopaminergic neurons survived the dissociation and grafting procedure in rats rendered hypothermic, but there was no significant additive effect on graft survival with a combined treatment. All groups of rats exhibited behavioral recovery in the amphetamine-induced rotation test. There was a significantly enhanced functional capacity of grafts placed in hypothermic as compared to normothermic rats. However, tirilazad/YVAD pretreated implants did not afford greater behavioral improvement than control-treated grafts. Our results suggest that neuroprotective treatments administered prior to and immediately after neural graft implantation may under certain conditions rescue, at least in part, the same subset of dopaminergic neurons. The study also emphasizes the importance of the immediate time after grafting for transplant survival, with relevance both for primary mesencephalic implants and stem cell grafts.

Keywords: Ac.YVAD.cmk; Dopamine; Lazaroid; Mesencephalic transplant; Parkinson's disease; Tirilazad mesylate

Document Type: Review Article

DOI: http://dx.doi.org/10.3727/000000005783983089

Affiliations: 1: Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, SE-221 84 Lund, Sweden, 2: Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, SE-221 84 Lund, Sweden 3: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University Hospital, SE-221 84 Lund, Sweden

Publication date: May 1, 2005

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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