Liposomal Formulations of Tacrolimus and Rapamycin Increase Graft Survival and Fiber Outgrowth of Dopaminergic Grafts

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Abstract:

The immunosuppressive drugs tacrolimus (TAC) and rapamycin (RAPA) have both been found to have neuroprotective effects on dopaminergic neurons. The purpose of the present study was to investigate whether liposomal formulations of these drugs administered directly into the brain improve cell survival and fiber outgrowth. Rats with unilateral 6-hydroxydopamine lesions were transplanted with 800,000 fetal rat ventral mesencephalic cells and randomly divided to one of four groups. Group 1 received a transplant containing cells only; group 2 received a cell suspension containing 0.68 μM liposomal RAPA (LRAPA); group 3 received a cell suspension containing 2.0 μM liposomal TAC (LTAC); and group 4 received a cell suspension containing a liposomal formulation of both 0.68 μM RAPA and 2.0 μM TAC (LRAPATAC). Rats were sacrificed after 6 weeks, and cell survival and fiber outgrowth were assessed using tyrosine hydroxylase (TH) immunohistochemistry. The animals receiving a cell suspension containing either LTAC or LRAPATAC were found to have significantly more surviving TH-immunoreactive (TH-ir) cells than the control group receiving cells only. The group receiving LTAC had significantly longer fibers, the group receiving LRAPA had significantly more fibers close to the graft, and the group receiving LRAPATAC had significantly more fibers at all distances. This study shows the feasibility of using liposomal formulations of neuroimmunophilins directly in the brain at the time of implantation to improve graft survival and fiber outgrowth. Furthermore, we have shown that the combination of LTAC and LRAPA has a synergistic effect. These compounds may play an important role in optimizing graft survival and host reinnervation in cell-mediated brain repair strategies for the treatment of neurological conditions.

Keywords: Liposomes; Parkinson’s disease; Rapamycin; Tacrolimus; Transplantation

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/000000004783983936

Affiliations: 1: *Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4H7 2: †Department of Surgery, Division of General Surgery, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 2Y9

Publication date: January 1, 2004

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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