Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease

Abstract

Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.

How to improve the survival of the fetal ventral mesencephalic cell transplanted in Parkinson’s disease?

“…The lazaroids, a group of compounds which have been developed for acute treatment of CNS injury, have been confirmed to improve the survival of grafted embryonic dopaminergic neurons by animal experiments [34] . Brundin and his colleagues found when tirilazad mesylate was administered to mesencephalic tissue prior to implantation and intravenously to patient for 3 d after surgery, the patients experienced the same improvement on functional performance and striatal [ 18 F] fluorodopa uptake as the previous patients who were implanted with twice much mesencephalic tissue [35] .…”

Cell Therapeutics in Parkinson's Disease

“…Similar to the time course of improvement in the open-label trials, grafted patients showed progressive symptomatic relief during the first 6 to 9 months after surgery, but then reverted back to baseline. The lack of efficacy could be explained by the patients of Olanow et al [14] being more severely disabled as compared to those, for example, in the Swedish series [4,8,18]. In support of this idea, Olanow et al [14] found significant improvement in their less severely disabled patients compared to the sham group at 2 years.…”

“…Neither in the open-label nor in the sham-surgery controlled clinical trials, improvements after intrastriatal transplantation of fetal mesencephalic DA-rich tissue in PD patients [4,6,8,9,13,14] have exceeded those found with DBS in the subthalamic nucleus [80]. Moreover, there is no Fig.…”

“…Dopaminergic Grafts Can Survive and Become Morphologically Integrated in the PD Patient's Brain Following implantation of postmitotic DA neuroblasts from the ventral mesencephalon of 6-to 9-weekold human fetuses, positron emission tomography (PET) detected increases in 6-L-[ 18 F]-fluorodopa ( 18 F-dopa) uptake ( Fig. 1) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and histopathological studies have shown long-term, extensive synaptic reinnervation in the striatum [13,[20][21][22][23][24][25][26][27].…”

“…In a group of PD patients, there was no evidence for abnormal DA release from the grafted neurons [29]. [4, 7-11, 13, 15-19, 31, 32], and the most successful cases have had L-dopa treatment withdrawn, exhibiting major clinical improvement for several years [4,8,18,28]. In contrast, the improvements in 2 sham surgerycontrolled clinical trials were only modest.…”