Tauroursodeoxycholic Acid Improves the Survival and Function of Nigral Transplants in a Rat Model of Parkinson's Disease

Abstract

There is accumulating evidence showing that the majority of cell death in neural grafts results from apoptosis when cells are implanted into the brain. Tauroursodeoxycholic acid (TUDCA), a taurine-conjugated hydrophilic bile acid, has been found to possess antiapoptotic properties. In the present study we have examined whether the supplementation of TUDCA to cell suspensions prior to transplantation can lead to enhanced survival of nigral grafts. We first conducted an in vitro study to examine the effects of TUDCA on the survival of dopamine neurons in serum-free conditions. The number of tyrosine hydroxylase (TH)-positive neurons in the TUDCA-treated cultures was significantly greater than that of control cultures 7 days in vitro. In addition, a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay showed that the number of apoptotic cells in the TUDCA-treated cultures was dramatically smaller than that in the control cultures. In the transplantation study, a 50 μM concentration of TUDCA was added to the media when nigral tissue from Sprague-Dawley (SD) rats was trypsinized and dissociated. Two microliters of cell suspension containing TUDCA was then stereotaxically injected into the striatum of adult SD rats subjected to an extensive unilateral 6-hydroxydopamine lesion of the nigrastriatal dopamine pathway. At 2 weeks after transplantation, the rats that received a cell suspension with TUDCA exhibited a significant reduction in amphetamine-induced rotation scores when compared with pretransplantation value. There was a significant increase (approximately threefold) in the number of TH-positive cells in the neural grafts for the TUDCA-treated group when compared with the controls 6 weeks postgrafting. The number of apoptotic cells was much smaller in the graft areas in the TUDCA-treated groups than in the control group 4 days after transplantation. These data demonstrate that pretreatment of the cell suspension with TUDCA can reduce apoptosis and increase the survival of grafted cells, resulting in an improvement of behavioral recovery.