Improving the Survival of Grafted Dopaminergic Neurons: A Review over Current Approaches

Abstract

Neural transplantation is developing into a therapeutic alternative in Parkinson's disease. A major limiting factor is that only 3-20% of grafted dopamine neurons survive the procedure. Recent advances regarding how and when the neurons die indicate that events preceding actual tissue implantation and during the first week thereafter are crucial, and that apoptosis plays a pivotal role. Triggers that may initiate neuronal death in grafts include donor tissue hypoxia and hypoglycemia, mechanical trauma, free radicals, growth factor deprivation, and excessive extracellular concentrations of excitatory amino acids in the host brain. Four distinct phases during grafting that can involve cell death have been identified: retrieval of the embryo; dissection and preparation of the donor tissue; implantation procedure followed by the immediate period after graft injection; and later stages of graft maturation. During these phases, cell death processes involving free radicals and caspase activation (leading to apoptosis) may be triggered, possibly involving an increase in intracellular calcium. We review different approaches that reduce cell death and increase survival of grafted neurons, typically by a factor of 2-4. For example, changes in transplantation procedure such as improved media and implantation technique can be beneficial. Calcium channel antagonists such as nimodipine and flunarizine improve nigral graft survival. Agents that counteract oxidative stress and its consequences, such as superoxide dismutase overexpression, and lazaroids can significantly increase the survival of transplanted dopamine neurons. Also, the inhibition of apoptosis by a caspase inhibitor has marked positive effects. Finally, basic fibroblast growth factor and members of the transforming growth factor-beta superfamily, such as glial cell line-derived neurotrophic factor, significantly improve the outcome of nigral transplants. These recent advances provide hope for improved survival of transplanted neurons in patients with Parkinson's disease, reducing the need for human embryonic donor tissue and increasing the likelihood of a successful outcome.

Ascorbic Acid Increases the Number of Dopamine Neurons In Vitro and in Transplants to the 6-OHDA-Lesioned Rat Brain

“…This low survival of dopamine neurons following transplantasites for graft placement, and the ability to restore full and homogenous dopaminergic innervation throughout tion means that for sufficient functional benefits to be achieved in Parkinson's disease patients, transplantation the striatum. One possible reason for the poor survival of dopaof mesencephalic tissue from four to eight human embryos is required per side of the brain (11). The requiremine neurons may be because of oxidative stress caused by free radicals, a mechanism that has been implicated ment for large quantities of human embryonic tissue for each patient makes widespread clinical delivery impracin the death of substantia nigra dopamine neurons in Parkinson's disease (16,29,33).…”

“…It is thought that oxidatical; therefore, increasing dopamine graft survival needs 764 BAGGA, DUNNETT, AND FRICKER-GATES tive stress caused by cellular trauma during dissection survival both in vitro and in grafts transplanted into the unilateral 6-OHDA-lesioned rat brain. Ascorbic acid and tissue preparation is one of the mechanisms contributing to poor neuronal survival, potentially by inducing was the only antioxidant used because previous reports have shown that the majority of dopamine cell death apoptosis in transplanted neurons (11,39). Removing cells from low oxygen environments and exposing them occurs over the first 24 h from cell dissociation, and this coincides with rapid ascorbic acid depletion in cultured to atmospheric oxygen levels of 20% during the dissection procedure may also promote oxidative stress and cells (23).…”

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

“…The death of the majority (~90-95%) of transplanted DA neurons from the fetal ventral mesencephalon (VM) soon after grafting in rat (Brundin et al, 2000) and human (Olanow et al, 1996) can serve to limit the success of the neural transplantation treatment strategy for Parkinson's disease. An important contributor to this poor survival appears to be the environment of the adult host brain, which may be less than optimal for the survival and growth of grafted immature neurons.…”

Long-term neuroretinal full-thickness transplants in a large animal model of severe retinitis pigmentosa

“…We chose to study transplantation of fetal instead of neonatal neuroretina to see if the greater plasticity of such tissue would enhance graft-host integration. Another rationale for using fetal donor tissue is that in contrast to neonatal tissue, it is available after ethical approval and has been used for clinical transplantation trials in RP patients as well as in patients suffering from Parkinson's disease [3,6]. To further promote graft-host integration, we used host eyes more severely affected by the disease, i.e with a retina in which very few of the rod photoreceptors remain, corresponding to an RP patient with a significant reduction in vision.…”