Brain Derived Neurotrophic Factor

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Brain-derived neurotrophic factor (BDNF), another member of the neurotrophin family (which includes NGF, NT-3, and NT-4/5), has been shown to have great potency in modulating the growth and survival of dopaminergic cells and their precursors. It is now widely accepted that the pluripotent BDNF and its high-affinity receptor trkB are widely distributed in both the developing and mature nervous system. Our increasing understanding of neurotrophin binding to their receptors, signal transduction following trk, and p75 dimerization and activation has lead to a series of exciting developments in designing experimental models to test novel trophic treatments. In addition to dopaminergic cells, BDNF was found to be potent on cholinergic and glutamatergic motor and sensory neurons, in both the central and peripheral nervous systems.

Among the most exciting new discoveries in the field of neurotrophic factor research is the ability of BDNF to be transported in an anterograde fashion. For example, it was shown that, in development, BDNF produced by dorsal interneurons stimulates the proliferation and differentiation of motor neuron progenitors after anterograde transport. Another piece of evidence comes from the studies by Kokaia et al., who have shown that BDNF levels increase significantly in a rat model of focal ischemia but then decrease rapidly, suggesting anterograde transport. Finally, additional supporting data for the anterograde transport of BDNF in the adult CNS were reported by Conner et al., who demonstrated that its distribution parallels axonal flow, including storage in terminals within the target.

One of the most important implications of antero-grade transport of BDNF is probably its participation in synaptic transmission. This theory is supported by data suggesting that enhancement of long-term transmission is manifested through synapse consolidation rather than neuronal growth. Also, in an in vitro explant model using hippocampal slice cultures,

Frerking et al., showed that BDNF may enhance transmission in CA1 neurons by decreasing the postsynaptic inhibition through a presynaptic mechanism. There is evidence that, at the presynaptic level, BDNF potentiation is mediated by cAMP. In addition, BDNF is reported to also be able to mediate agrin-induced postsynaptic differentiation. All of these functions obviously can be critical steps in the establishment of a functional cell graft.

In spinal cord injuries, neurotrophin treatments are proposed to present significant clinical benefits. For example, BDNF infused at the site ofspinal cord injury in rats showed a positive but transient effect on local reflexes. The most dramatic impact of BDNF occurred in fully transected spinal cords. When these chronic infusions were stopped, the behavioral effects disappeared. BDNF was also shown to stimulate sprouting ofcholinergic fibers at the injury site, but did not affect serotonergic fibers or total axon density. In an effort to promote directional regeneration, cells transformed to secrete BDNF were grafted in trails in the transected spinal cord, and the results showed a significant positive effect on axons from trkB expressing neurons. In another study by Broude et al., it was shown that in spinal cord transplants the addition of BDNF increased axonal outgrowth of axotomized neurons.

BDNF has been proposed to have an autocrine effect on dopaminergic neurons that express abundant trkB, and if these results are confirmed in humans, new hypotheses may be formulated about the mechanisms of disease in parkinsonism. Supporting this theory, several studies showed reduced BDNF protein in the substantia nigra of PD patients. In this context, BDNF treatments (similar to GDNF, discussed later) pre- and posttransplantation may serve a dual purpose: stimulate the growth of a functional dopaminergic population within the graft and promote the regeneration of dopaminergic pathways in PD.

Interestingly, some reports suggested that BDNF enhanced the function rather than survival ofthe grafts enriched with dopamine cells. In vitro, BDNF can protect dopaminergic neurons from hydroxydopa-mine toxicity. In vivo, similar protective functions were observed in rats with BDNF producing grafts, after being challenged with the active metabolite of the dopaminergic toxin MPTP. The regenerative capacity of BDNF on dopaminergic projections was shown to be both direct and indirect, mediated through improved fetal grafts. Still, only a subpopulation of nigral dopaminergic cells may be susceptible to these effects, depending on their capacity to express the high-affinity receptor trkB. Furthermore, there are some concerns ab out the effects of long-term in situ delivery of BDNF in vivo, at least in the rat striatum. Currently, it still appears that the most consistently positive use of BDNF in cell transplantation is to promote dopami-nergic differentiation preimplantation. When rat and human nigral fetal cell aggregates were treated with BDNF, the number of TH-positive neurons increased significantly. These effects were further enhanced when GDNF was used in combination with BDNF.

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