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      Current advances in using neurotrophic factors to treat neurodegenerative disorders

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          Abstract

          Neurotrophic factors are best known for their roles in both development and continued maintenance of the nervous system. Their strong potential to elicit pro-survival and pro-functional responses in neurons of the peripheral and central nervous system make them good drug candidates for treatment of a multitude of neurodegenerative disorders. However, significant obstacles remain and need to be overcome before translating the potential of neurotrophins into the therapeutic arena. This article addresses current efforts and advances in resolving these challenges and provides an overview of roadmaps for future translational research and neurotrophin-based drug developments.

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          Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease.

          Alan Nagahara, David Merrill, Giovanni Coppola … (2009)
          Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.
          Article 0 comments Cited 273 times – based on 0 reviews     Review now
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            A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease.

            Mark H. Tuszynski, Leon Thal, Mary Pay … (2005)
            Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.
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              BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra.

              C Hyman, M Hofer, Y Barde … (1991)
              Brain-derived neurotrophic factor (BDNF), present in minute amounts in the adult central nervous system, is a member of the nerve growth factor (NGF) family, which includes neurotrophin-3 (NT-3). NGF, BDNF and NT-3 all support survival of subpopulations of neural crest-derived sensory neurons; most sympathetic neurons are responsive to NGF, but not to BDNF; NT-3 and BDNF, but not NGF, promote survival of sensory neurons of the nodose ganglion. BDNF, but not NGF, supports the survival of cultured retinal ganglion cells but both NGF and BDNF promote the survival of septal cholinergic neurons in vitro. However, knowledge of their precise physiological role in development and maintenance of the nervous system neurons is still limited. The BDNF gene is expressed in many regions of the adult CNS, including the striatum. A protein partially purified from bovine striatum, a target of nigral dopaminergic neurons, with characteristics apparently similar to those of BDNF, can enhance the survival of dopaminergic neurons in mesencephalic cultures. BDNF seems to be a trophic factor for mesencephalic dopaminergic neurons, increasing their survival, including that of neuronal cells which degenerate in Parkinson's disease. Here we report the effects of BDNF on the survival of dopaminergic neurons of the developing substantia nigra.
              Article 0 comments Cited 153 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Transl Neurodegener
                Journal ID (iso-abbrev): Transl Neurodegener
                Title: Translational Neurodegeneration
                Publisher: BioMed Central
                ISSN (Electronic): 2047-9158
                Publication date Collection: 2012
                Publication date (Electronic): 26 July 2012
                Volume: 1
                Page: 14
                Affiliations
                [1 ]Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, 92093-0649, USA
                [2 ]Department of Neurosciences, University of California San Diego, George Palade Labs (GPL), Room 337 MC-0649, 9500 Gilman Drive, La Jolla, CA, 92093, USA
                Article
                Publisher ID: 2047-9158-1-14
                DOI: 10.1186/2047-9158-1-14
                PMC ID: 3542569
                PubMed ID: 23210531
                SO-VID: 5565b41d-5a31-4204-862b-35ef19d6717b
                Copyright © Copyright ©2012 Weissmiller and Wu; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 8 June 2012
                Date accepted : 26 July 2012
                Categories
                Subject: Review

                ScienceOpen disciplines: Neurosciences
                Keywords: bdnf,neurotrophin,mimetics,gene delivery,neurotrophic factor,ngf
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: bdnf, neurotrophin, mimetics, gene delivery, neurotrophic factor, ngf

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