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GDNF, NGF and BDNF as therapeutic options for neurodegeneration

Significance Statement

The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and the growth factor glial cell-derived neurotrophic factor (GDNF), have variously been considered as therapeutic options for Alzheimer’s (AD), Parkinson’s (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). This review discusses these three proteins and their roles in the adult brain. Each is important for the maintenance of function of specific neuronal types: GDNF and BDNF are neurotrophic for dopaminergic and motor neurons and BDNF and NGF for cholinergic basal forebrain neurons. BDNF also has a pivotal function in long term potentiation, memory formation and synaptic plasticity. In AD there is evidence that the precursors of NGF and BDNF (proneurotrophins), have a possible role in the neurodegenerative disease process; this and other causes of neurodegeneration are examined and the present and future therapies available. Successful therapeutic administration of these proteins is difficult as it requires them to be placed within the brain parenchyma or the CSF; due to their size and nature, they will not readily pass through the blood-brain-barrier. These difficulties are described and new methods of treatment presented.  For instance, sub optimal delivery of GDNF protein for PD is being improved by the development of convection enhanced delivery (CED). Use of NGF for AD has been considered since the early 1990s; initial trials using intraventricular administration of NGF protein were superseded by implantation of fibroblasts secreting NGF near the cholinergic basal forebrain. This is now being progressed to clinical trials with adeno-associated virus-mediated delivery of NGF constructs. BDNF has been used successfully in preclinical models of AD, although there are likely to be considerations accompanying its use in clinical trials, one of which is the high level of truncated BDNF receptors which readily sequester it in the brain. Concurrently there has been a search for small molecule agonists or modulators at the NGF and BDNF receptors, TrkA and TrkB, to provide a viable alternative to using proteins. In this review, these three neurotrophic factors are discussed in terms of their mechanism of action, signalling pathways and their likelihood to act as therapeutics in the near future.

Figure 1.  Representations of the X-ray crystal structures of [A] NGF: green and blue ribbons showing two monomers, side chains are shown in yellow and blue (modelled from 1WWW.pdb) [B] BDNF: green and blue ribbons showing two monomers, side chains are shown in mauve and cerise (from 1BND.pdb) and [C] GDNF: cerise and red ribbons showing two monomers end on, side chains are shown in pink or green (from 2V5E.pdb).

 

GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Global Medical Discovery

 

 

 

 

 

 

 

 

 

Journal Reference

Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. Pharmacol Ther. 2013 May;138(2):155-75.

Dorothy Hodgkin Building, Whitson St, Bristol BS1 3NY, UK. [email protected]

Abstract

Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s diseases. GDNF administration has recently been shown to be an effective treatment for Parkinson’s disease, with clinical trials currently in progress. Trials with NGF for Alzheimer’s disease are ongoing, with some degree of success. Preclinical results using BDNF also show much promise, although there are accompanying difficulties. Ultimately, the administration of a therapy involving proteins in the brain has inherent problems. Because of the blood-brain-barrier, the protein must be infused directly, produced by viral constructs, secreted from implanted protein-secreting cells or actively transported across the brain. An alternative to this is the use of a small molecule agonist, a modulator or enhancer targeting the associated receptors. We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process.

Copyright © 2013 Elsevier Inc. All rights reserved.

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