Glial Derived Neurotrophic Factor

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In general, GDNF has similar or even enhanced trophic functions on dopaminergic neurons and their precursors. In vivo, GDNF was also shown to be relatively potent in animal models of dopaminergic protection or regeneration, but human clinical trials have not been so encouraging. Nonetheless, its potential use in PD has made GDNF the prime candidate for NTF treatments in association with fetal mesencepha-lic transplants of dopaminergic neurons.

GDNF, a related member of the TGF-b family, was first identified and characterized in 1993 by Lin et al. From the beginning, it was evident that GDNF has a potent but specific-selective activity on dopaminergic neurons, inducing their differentiation in the absence of overt neuroglial proliferation. Shortly after, in vivo studies demonstrated that GDNF injected into the substantia nigra produced a significant decrease in the motor deficits associated with 6-OHDA lesioning in rats. When GDNF was injected in developing or mature mesencephalic grafts, in oculo, its primary effect was to promote dopaminergic neuritic growth rather than survival of TH-positive cells. Interestingly, administration of GDNF in a murine MPTP parkin-sonian model had both protective and regenerative effects. The in vivo protective effects were also demonstrated in a rat nigral axotomy model, suggesting again that GDNF has a high specificity for dopaminergic neurons.

Further in vitro studies showed that a mixture of slow-release GDNF, fibrin glue, and fetal mesence-phalic neuroglial cells resulted in a significant increase in the number of TH-positive cells and neuritic density. Another in vitro study indicated that GDNF may offer protection from continuous cell death after the removal of toxins and even stimulate dopaminergic fiber regrowth. When another neurotoxin, quinolinic acid, was used, GDNF showed selective protection of dopaminergic neurons against excitotoxicity.

In vivo studies using fetal mesencephalic grafts showed that injections of GDNF in the vicinity of the rat brain implant resulted in significantly increased survival and growth of TH-positive cells accompanied by marked functional improvement. The improved survival and differentiation of dopaminergic fetal grafts treated with GDNF pre- or postimplantation have been independently confirmed in numerous studies focused on the therapeutic benefits in parkin-sonian models. A more recently identified member of this family of growth factors, neurturin, was found to be similarly potent in preventing dopaminergic cell death but lacked the support for TH-positive neuritic growth associated with GDNF treatments. Finally, in clinical studies, two patients with PD who received fetal dopaminergic implants pretreated in vitro with GDNF showed increased graft survival. The benefits of GDNF treatments in PD patients appear to be restricted to association with fetal grafts. When GDNF was injected into the cerebroventricular system of a PD patient that did not receive a graft, the results appeared detrimental. Further research is continuing on this approach.

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