Article

GDNF, NGF and BDNF as therapeutic options for neurodegeneration

Dorothy Hodgkin Building, Whitson St, Bristol BS1 3NY UK. Electronic address: .
Pharmacology [?] Therapeutics (Impact Factor: 7.75). 01/2013; 138(2). DOI: 10.1016/j.pharmthera.2013.01.004
Source: PubMed

ABSTRACT Glial cell-derived neurotrophic factor (GDNF), and the neurotrophins 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 disease. 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 into 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.

0 Followers
 · 
311 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism/catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches.
    Antioxidants & Redox Signaling 02/2009; 11(7):1569-86. DOI:10.1089/ARS.2008.2414 · 7.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of adult mammal central nervous system (CNS) is closely related to loosing the ability spontaneously regenerate after injuries. On the other hand, peripheral nervous system (PNS) maintains its capability to regenerate after injuries entire lifespan. Ability to regenerate successfully is mainly determined by the balance of growth promoting and growth inhibiting factors, expressed by both neuronal and non-neuronal cells found in the injury site. Some of signaling cues involved in regeneration are expressed in adult CNS constantly, although expression of other factors occurs only in the injury site of adult mammal. Ephrins, Semaphorins, Slits and Netrins are among most important molecules involved in lack of success in regeneration of CNS. PNS neurons initiate reparation mechanisms right after development of injury, and are capable to recover functional activity even if an area of injury is more than several centimeters wide. Understanding of differences between CNS and PNS regeneration and factors involved in functional nervous system recovery are crucial for both in depth analysis of plasticity of adult mammal neural system, and for developing new treatment strategies.
    Biologija 06/2013; 59(1):1-14. DOI:10.6001/biologija.v59i1.2647
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Compelling evidence exists that non-haematopoietic stem cells, including mesenchymal (MSCs) and neural/progenitor stem cells (NPCs), exert a substantial beneficial and therapeutic effect after transplantation in experimental central nervous system (CNS) disease models through the secretion of immune modulatory or neurotrophic paracrine factors. This paracrine hypothesis has inspired an alternative outlook on the use of stem cells in regenerative neurology. In this paradigm, significant repair of the injured brain may be achieved by injecting the biologics secreted by stem cells (secretome), rather than implanting stem cells themselves for direct cell replacement. The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues. Thanks to recent improvements in SCS profiling and manipulation, investigators are now inspired to harness the SCS as a novel alternative therapeutic option that might ensure more efficient outcomes than current stem cell-based therapies for CNS repair. This review discusses the most recent identification of MSC- and NPC-secreted factors, including those that are trafficked within extracellular membrane vesicles (EVs), and reflects on their potential effects on brain repair. It also examines some of the most convincing advances in molecular profiling that have enabled mapping of the SCS.
    Biochimie 07/2013; 95(12). DOI:10.1016/j.biochi.2013.06.020 · 3.12 Impact Factor
Show more