GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther

Dorothy Hodgkin Building, Whitson St, Bristol BS1 3NY UK. Electronic address: .
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 01/2013; 138(2). DOI: 10.1016/j.pharmthera.2013.01.004
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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.

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    • "A large body of evidences indicates that reduced expression of neurotrophins and changes in the level of their receptors can lead to dysregulation of neuronal function, and neuronal death can lead to the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Scaper 2008; Bruno et al. 2009; Calissano et al. 2010). Therefore, the possibility to upregulate the level of neuroprotective substances, such as NGF, BDNF, and IL-6 is one of the key aspects to improve nervous system development and function, and can be a promising goal in the therapy of neurodegenerative diseases , in which a decreased level of neurotrophins is observed (Lessmann et al. 2003; Aloe et al. 2012; Allen et al. 2013). Because of difficulties with the use of recombinant neurotrophins in the therapy, increasing attention has been turned to alternative strategies. "
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    ABSTRACT: Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor, as well as cytokines, for example, interleukin-6 (IL-6) play an important role in neuroprotection and in the control of the central nervous system (CNS) function. Reduced expression of neurotrophic factors can lead to dysregulation of neuron function and neuronal death. There is also evidence for mutual interactions between neurotrophins and IL-6. Therefore, the up-regulating the level of neuroprotective substances is one of the key manners to control the nervous system development and function. It can be a promising aim in the therapy of neurodegenerative disease in which the decreased level of neurotrophins is observed. In our recent studies, the role of proline-rich polypeptide complex (PRP) and its nonapeptide fragment (NP) in the regulation of neurotrophic activity in cultured astrocytes was shown. PRP and NP stimulate human astrocytoma cell line U87 to release the significant amounts of NGF to the extracellular space both in its precursor and mature form. We also provide the evidence that in NP-treated cells, the level of βNGF mRNA was increased. NP-treated cells used in this study produced also increasing amounts of IL-6. This finding indicates that PRP and its nonapeptide fragment NP up-regulate neurotrophic activity of U87 cell line by increase of NGF synthesis and its release into the extracellular space. It was also shown that NP-dependent increased production of IL-6 can enhance the NGF activity.
    Cellular and Molecular Neurobiology 04/2015; 35(7). DOI:10.1007/s10571-015-0192-8 · 2.51 Impact Factor
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    • "Several studies have confirmed that brief bouts of (intense) aerobic exercise result in a transient increase in circulating IGF-1 and BDNF. Gene expression and secretion of BDNF in the brain is mainly regulated in an activity-dependent manner, which might explain why BDNF, among all neurotrophins, is most consistently upregulated with exercise (Allen et al. 2013). The mechanisms/ stimuli responsible for this exercise-induced increase have not yet been clearly established, but some hypotheses are proposed in literature. "
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    ABSTRACT: Exercise is known to have beneficial effects on cognitive function. This effect is greatly favored by an exercise-induced increase in neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), especially with high-intensity exercises (HIE). As a complication of type 1 diabetes (T1D), a cognitive decline may occur, mostly ascribed to hypoglycaemia and chronic hyperglycaemia. Therefore, the purpose of this study was to examine the effects of acute HIE on cognitive function and neurotrophins in T1D and matched controls. Ten trained T1D (8 males, 2 females) participants and their matched (by age, sex, fitness level) controls were evaluated on 2 occasions after familiarization: a maximal test to exhaustion and an HIE bout (10 intervals of 60 s at 90% of their maximal wattage followed by 60 s at 50 W). Cognitive tests and analyses of serum BDNF, IGF-1, and free insulin were performed before and after HIE and following 30 min of recovery. At baseline, cognitive performance was better in the controls compared with the T1D participants (p < 0.05). After exercise, no significant differences in cognitive performance were detected. BDNF levels were significantly higher and IGF-1 levels were significantly lower in T1D compared with the control group (p < 0.05) at all time points. Exercise increased BDNF and IGF-1 levels in a comparable percentage in both groups (p < 0.05). In conclusion, although resting levels of serum BDNF and IGF-1 were altered by T1D, comparable increasing effects on BDNF and IGF-1 in T1D and healthy participants were found. Therefore, regularly repeating acute HIE could be a promising strategy for brain health in T1D.
    Applied Physiology Nutrition and Metabolism 01/2015; 40(1). DOI:10.1139/apnm-2014-0098 · 2.34 Impact Factor
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    • "To verify that PB-IPCs-derived astrocyte-like cells possess neurotrophic functions, we tested the mRNA expression of several neurotrophic factors, including BDNF, NGF and GDNF, which play important protective roles in some neurodegenerative diseases, such as Alzheimer's and Parkinson's (Allen et al., 2013). BDNF mRNA is more strongly expressed in PB-IPCs than GDNF or NGF mRNA. "
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    ABSTRACT: We have previously reported a novel CD45-positive cell population called peripheral blood insulin-producing cells (PB-IPCs) and its unique potential for releasing insulin in vitro. Despite the CD45-positive phenotype and self-renewal ability, PB-IPCs are distinguished from hemopoietic and endothelial progenitor cells (EPCs) by some characteristics, such as a CD34-negative phenotype and different culture conditions. We have further identified the gene profiles of the embryonic and neural stem cells, and these profiles include Sox2, Nanog, c-Myc, Klf4, Notch1 and Mash1. After treatment with all-trans retinoic acid (ATRA) in vitro, most PB-IPCs exhibited morphological changes that included the development of elongated and branched cell processes. In the process of induction, the mRNA expression of Hes1 was robustly upregulated, and a majority of cells acquired some astrocyte-associated specific phenotypes including anti-glial fibrillary acidic protein (GFAP), CD44, Glutamate-aspartate transporter (GLAST) and S100β. In spite of the deficiency of glutamate uptaking, the differentiated cells significantly relaxed the regulation of the expression of brain-derived neurotrophic factor (BDNF) mRNA. This finding demonstrates that PB-IPCs could be induced into a population of astrocyte-like cells and enhanced the neurotrophic potential when the state of proliferation was limited by ATRA, which implicates that this unique CD45+ cell pool may have a protective role in some degenerative diseases of the central nervous system (CNS).
    Cell Biology International 01/2015; 39(1). DOI:10.1002/cbin.10355 · 1.93 Impact Factor
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