S ince their discovery, putative roles of the neurotrophic factors have been extensively explored in the CNS and PNS. Localization of the factors and their receptors and their putative roles have been and are being investigated with a wide variety of techniques. The advent of molecular biological techniques, including the propagation of transgenic mice with selective or generalized over- or underexpression or deletion, has been instrumental in demonstrating the vital and complex role that the neurotrophic factors play in differentiation and survival of
Paul F. Morrison, Russell R. Lonser and Edward H. Oldfield
evaluations of patient responses based on standardized assessments. Despite these similarities, authors of these trials reached contrasting conclusions regarding the efficacy of GDNF for the treatment of PD. The results of two small open-label studies 28 , 33 indicated that local delivery of the neurotrophic factor leads to sufficient improvement in patient status to warrant further clinical investigation, whereas the findings of a more recent randomized controlled clinical trial 18 demonstrated no difference in the primary or secondary end points, leading the
Christina K. Magill, Amy M. Moore, Ying Yan, Alice Y. Tong, Matthew R. MacEwan, Andrew Yee, Ayato Hayashi, Daniel A. Hunter, Wilson Z. Ray, Philip J. Johnson, Alexander Parsadanian, Terence M. Myckatyn and Susan E. Mackinnon
S urgical treatment of devastating peripheral nerve injuries currently relies on a combination of nerve grafting and nerve transfer procedures. A better understanding of neurotrophic factors and their effects on regeneration is likely to provide the next paradigm shift in the treatment of peripheral nerve injuries. Glial cell line–derived neurotrophic factor is a well-known member of the GDNF family of ligands, which has demonstrated neuroprotective and regenerative properties in a number of PNS and CNS disease and injury models. 5 , 28 , 33 , 37 , 42 , 55
Bum-Tae Kim, Vemuganti L. Raghavendra Rao, Kurt A. Sailor, Kellie K. Bowen and Robert J. Dempsey
at subtypes of glutamate receptors, free radical scavengers, and calcium channel blockers. 5, 18 The search for an ideal candidate drug continues, however, because no drug has been conclusively shown to be neuroprotective in human TBI without undesirable side effects. 7 Much attention has been focused recently on the neurotrophic factors to prevent neuronal death after TBI. 29, 32 Neurotrophic factors include neurotrophins, cytokines, and members of the fibroblast growth factor and TGFβ super-family. 16 The first member of a new family of trophic factors
Fu-Chou Cheng, Ming-Hong Tai, Meei-Ling Sheu, Chun-Jung Chen, Dar-Yu Yang, Hong-Lin Su, Shu-Peng Ho, Shu-Zhen Lai and Hung-Chuan Pan
S everal approaches have been proposed to exert beneficial effects on peripheral nerve regeneration, including application of an electric field, transplantation of stem cells, and administration of neurotrophic factors. 24 , 29 , 31 , 33 The implantation of embryonic stem cells, neural stem cells, and mesenchymal stem cells has been shown to exert favorable effects on peripheral nerve regeneration. Cell replacement, trophic factor production, extracellular matrix molecule synthesis, guidance, remyelination, microenvironmental stabilization, and immune
Young Mi Yoo, Yong Jung Kim, Uhn Lee, Doo Jin Paik, Hyun Tae Yoo, Cheol Wan Park, Young Bo Kim, Sang Goo Lee, Woo Kyung Kim and Chan Jong Yoo
Parkinson disease (PD) is a well-known degenerative disease resulting in the depletion of dopamine-producing neurons in the pars compacta of the substantia nigra. Adenoviral vector delivery of neurotrophic factors may provide a potential therapy for PD. The authors examined whether glial cell line–derived neurotrophic factor (GDNF) delivered via adenoviral vector (Ad-GDNF) could promote functional recovery in a rat model of PD. Additionally, they examined whether neural precursor cells (NPCs) provide the therapeutic potential of cultured neural cells for cell regeneration and replacement in PD.
All animals underwent stereotactic injection of 6-hydroxydopamine into the right substantia nigra. Eight weeks later, the rats were tested for apomorphine-induced rotational asymmetry and evaluation of explanted grafts infected with the complementary DNA for GDNF containing NPCs and NPCs alone. In the NPC cultures of embryonic rat striata, the authors found that basic fibroblast growth factor induced the proliferation of stem cells, which give rise to spheres of undifferentiated cells that generate neurons and glia.
In this study the authors found that the reduction of apomorphine-induced rotation was more prominent in parkinsonian rats that received Ad-GDNF-treated grafts containing NPCs (61%) than in those that received grafts of NPCs alone (16%).
Takao Yasuhara, Tetsuro Shingo, Kenichiro Muraoka, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Yuan WenJi, Masahiro Kameda, Toshihiro Matsui, Yasuyuki Miyoshi and Isao Date
T wo double-blind controlled trials of fetal nigral transplantation in patients with PD have revealed a limitation of the therapy. 10, 26 The transplantation induced a dyskinesia in many patients and only showed a significant improvement in Unified Parkinson's Disease Rating Scale scores in younger patients. Glial cell line—derived neurotrophic factor is now being reevaluated as a hopeful molecule for the treatment of PD. This molecule has been reported to confer neuroprotective effects on dopaminergic neurons in an animal model of PD, 27, 29 although
Vivek Mehta, Murray Hong, Julian Spears and Ivar Mendez
using such factors in conjunction with neural transplantation for the treatment of degenerative disorders such as PD. The newest member of the transforming factor—β superfamily, glial cell line—derived neurotrophic factor (GDNF), is a potent neurotrophin that has demonstrated the ability to increase midbrain dopamine levels, protect dopaminergic neurons, and increase fiber outgrowth both in vitro and in vivo. 8, 11, 12, 14, 15, 25 We have recently demonstrated that storage of fetal dopaminergic cells in a GDNF-rich hibernation medium for 6 days enhances graft
John T. Slevin, Greg A. Gerhardt, Charles D. Smith, Don M. Gash, Richard Kryscio and Byron Young
C urrently available treatments for PD become increasingly less efficacious as the disease progresses and do little to slow the underlying pathophysiological changes in the nigrostriatal dopaminergic system. 33, 34 Neurotrophic factors—proteins that activate cell signaling pathways regulating neuronal survival, differentiation, growth, and regeneration—represent a promising alternative for treating dopaminergic neurons in PD but are difficult to administer clinically because they do not pass through the blood-brain barrier. 4, 6 Glial cell line
Adam O. Hebb, Kari Hebb, Arun C. Ramachandran and Ivar Mendez
-immunoreactive cells per graft, when compared with transplants of fresh VM tissue grafted with (but not stored in) GDNF. These data seem to indicate that the antiapoptotic actions of GDNF require the de novo synthesis of proteins. Preincubation with neurotrophic factors may rescue a population of cells that die early in hibernation or in transplanted grafts. Sauer and Brundin 43 noted that, although there was a significant decrease in TH-immunoreactive cell populations of VM stored for 24 hours, as determined using cell smear immunohistochemical studies, there was no difference