Attempts to enhance survival of transplanted dopamine neurons

Only about 5% of neurons in the SNc are dopaminergic, and only about 5-20% of grafted dopamine neurons survive transplantation (Kordower et al., 1998; Sortwell et al., 2004). Approximately 20-30% of mes-encephalic cells die during preparation of the tissue for transplantation probably due to ischemia or trauma associated with dissection and dissociation of the cells (Fawcett et al., 1995; Brundin et al., 2000a) and another 60-70% of cells die during the first week post-transplantation (Barker et al., 1996; Sortwell et al., 2000). Enhanced survival of transplanted cells would facilitate the logistics of performing a fetal nigral transplant procedure and could potentially yield enhanced clinical results. Considerable research has focused on ways of trying to improve this yield. Mesencephalic cell graft aggregates can be maintained in culture and exposed to agents such as antioxidants and trophic factors that promote their survival that promote their survival following transplantation (Meyer et al., 1998).

Neurotrophic factors promote the survival of dopaminergic neurons in vitro and in vivo (Lin et al., 1993; Nikkhah et al., 1993; Altar et al., 1994; Studer et al., 1995) and might therefore be expected to enhance survival and functional effects of dopamine cell transplants. Trophic factors can be administered by direct infusion into the striatum, through co-transplantation of cells that manufacture and secrete neurotrophic factors, and by gene therapy approaches. Approximately 94% of melanized neurons within the SNc normally contain fibroblast growth factor 2 (FGF-2) receptors suggesting this might be an important trophic factor for dopamine neurons (Tooyama et al., 1994). Indeed, co-transplantation of Schwann cells that express FGF-2 enhances the survival of intrastriatal dopamine grafts and promotes striatal reinnervation and functional recovery in the rat model of PD (Timmer et al., 2004). Glial derived neurotrophic factor (GDNF) is a member of the transforming growth factor p family and appears to have the greatest capacity amongst trophic factors to protect dopaminergic neurons both in culture and in vivo. GDNF infusion in MPTP lesioned primates enhances survival of nigral neurons, increases TH staining in the striatum, and improves behavioral features even when delivered weeks after the insult (Gash et al., 1995; 1996; Winkler et al., 1996). Lentivirus delivery of GDNF similarly is associated with marked behavioral and anatomic benefits in both the 6-OHDA rodent and the MPTP monkey (Bensadoun et al., 2000; Kordower et al., 2000). GDNF has been shown to improve survival of grafted dopamine neurons and to increase striatal reinnervation in the 6-OHDA rat (Granholm et al., 1997; Zawada et al., 1998), suggesting that co-administration of GDNF might be a way to enhance the clinical effects associated with fetal nigral grafts. The carotid body contains DA rich chromaffin cells which release neurotrophic factors such as GDNF, as well as brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). Co-transplantation of carotid body cells has been shown to enhance the survival of grafted fetal ventral mesencephalic dopaminergic cells, striatal TH immunoreactivity and dopamine levels, and functional recovery in 6-OHDA lesioned rats (Shukla et al., 2004). Encapsulated cells that constitu-tively express high levels of VEGF have also been reported to improve behavior and decrease TH cell loss in a rat model of PD, but have not been tested in conjunction with transplanted dopamine cells (Yasuhara et al., 2004).

Increased expression or co-administration of anti-apoptotic and antioxidant agents is another approach that has been tried in an attempt to increase the survival of transplanted dopamine neurons. The Jun-N-terminal kinase (JNK) stress pathway is central to apoptotic neuronal death in several model systems (Chun et al., 2001; Gearan et al., 2001) and mixed lineage kinase (MLK) activation is a critical event in this sequence of events (Xu et al., 2001). MLK inhibitors have been shown to protect against dopaminergic cell death in culture systems (Harris et al., 2002; Murakata et al., 2002), and to improve long-term survival, graft size and fiber outgrowth following transplantation of rat ventral mesenecephalic cells (Boll et al., 2004). Caspase inhibitors also reduce apoptosis in many model systems and increase the survival of dopaminergic grafts in the 6-OHDA rat model (Schierle et al., 1999). Antioxidants also improve graft survival, striatal TH-immunoreactivity and behavioral function when co-administered with ventral mesencephalic grafts (Agrawal et al., 2004). Co-administration of lazaroids with fetal nigral transplantation has now been attempted in PD patients with good clinical results (Brundin et al., 2000b), but it is not possible to say with any certainty how much the lazaroids contributed to the observed benefit based on this anecdotal report.

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