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      Exploring Serum Levels of Brain Derived Neurotrophic Factor and Nerve Growth Factor Across Glaucoma Stages

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          Abstract

          Purpose

          To investigate the serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in patients affected by primary open angle glaucoma with a wide spectrum of disease severity compared to healthy controls and to explore their relationship with morphological and functional glaucoma parameters.

          Materials and Methods

          45 patients affected by glaucoma at different stages and 15 age-matched healthy control subjects underwent visual field testing, peripapillary retinal nerve fibre layer thickness measurement using Spectral Domain Optical Coherence Tomography and blood collection for both neurotrophins detection by Enzyme-Linked Immunosorbent Assay. Statistical analysis and association between biostrumental and biochemical data were investigated.

          Results

          Serum levels of BDNF in glaucoma patients were significantly lower than those measured in healthy controls (261.2±75.0 pg/ml vs 313.6±79.6 pg/ml, p = 0.03). Subgroups analysis showed that serum levels of BDNF were significantly lower in early (253.8±40.7 pg/ml, p = 0.019) and moderate glaucoma (231.3±54.3 pg/ml, p = 0.04) but not in advanced glaucoma (296.2±103.1 pg/ml, p = 0.06) compared to healthy controls.

          Serum levels of NGF in glaucoma patients were significantly lower than those measured in the healthy controls (4.1±1 pg/mL vs 5.5±1.2 pg/mL, p = 0.01). Subgroups analysis showed that serum levels of NGF were significantly lower in early (3.5±0.9 pg/mL, p = 0.0008) and moderate glaucoma (3.8±0.7 pg/ml, p<0.0001) but not in advanced glaucoma (5.0±0.7 pg/ml, p = 0.32) compared to healthy controls.

          BDNF serum levels were not related to age, visual field mean deviation or retinal nerve fibre layer thickness either in glaucoma or in controls while NGF levels were significantly related to visual field mean deviation in the glaucoma group (r 2 = 0.26, p = 0.004).

          Conclusions

          BDNF and NGF serum levels are reduced in the early and moderate glaucoma stages, suggesting the possibility that both factors could be further investigated as potential circulating biomarkers for the early detection of glaucoma.

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          Most cited references33

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          Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.

          The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
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            The impact of age, weight and gender on BDNF levels in human platelets and plasma.

            Brain-derived neurotrophic factor (BDNF) is a key mediator of neuronal plasticity in the adult. BDNF is known to be stored in human platelets and to circulate in plasma, but the regulation and function of BDNF in peripheral blood is still poorly understood. In this prospective study, we have examined 140 healthy, non-allergic adults (20-60 years old) to elucidate the impact of age and physical parameters on BDNF levels in human platelets and plasma. There was a wide concentration range of BDNF in serum (median: 22.6 ng/ml), platelets (median: 92.7 pg/10(6) platelets) and plasma (median: 92.5 pg/ml). BDNF levels in plasma decreased significantly with increasing age or weight, whereas platelet levels did not. When matched for weight, there were no significant gender differences regarding BDNF plasma levels. However, women displayed significantly lower platelet BDNF levels than men. In addition, platelet BDNF levels changed during the menstrual cycle. In conclusion, we demonstrate that parameters such as age or gender have a specific impact on stored and circulating BDNF levels in peripheral blood.
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              Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.

              Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions. These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase-polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas. Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain. Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 January 2017
                2017
                : 12
                : 1
                : e0168565
                Affiliations
                [1 ]IRCCS-Fondazione GB Bietti, Rome, Italy
                [2 ]Department of Ophthalmology, Campus Bio-Medico University, Rome, Italy
                [3 ]Section of Ophthalmology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health University of Brescia, Brescia, Italy
                [4 ]Ophthalmology Clinic, Department of Medicine and Aging Science, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
                [5 ]DSCMT, University of Rome Tor Vergata, Rome, Italy
                Massachusetts Eye & Ear Infirmary, Harvard Medical School, UNITED STATES
                Author notes

                Competing Interests: Yes, Prof. Stefano Bonini reports personal financial interest with DOMPE', outside the submitted work. In addition, Prof. Stefano Bonini has a patent hrNGF with royalties paid to Dompè, Italy. We confirm that Prof. Stefano Bonini's competing interests don’t alter our adherence to all PLOS ONE policies on sharing data and materials.

                • Conceptualization: GR FO AM SB.

                • Formal analysis: FO GR.

                • Investigation: GR AM.

                • Methodology: AM GR SB.

                • Project administration: FO SB GM.

                • Resources: AM AB.

                • Supervision: FO.

                • Validation: LQ LA.

                • Visualization: GR.

                • Writing – original draft: FO GR.

                • Writing – review & editing: GM SB.

                Article
                PONE-D-16-28823
                10.1371/journal.pone.0168565
                5221757
                28068360
                2b5507da-a110-4c9c-996c-0644c386bd8f
                © 2017 Oddone et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 July 2016
                : 3 December 2016
                Page count
                Figures: 2, Tables: 4, Pages: 14
                Funding
                The research for this paper was financially supported by the Italian Ministry of Health and by Fondazione Roma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Ophthalmology
                Eye Diseases
                Glaucoma
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Afferent Neurons
                Retinal Ganglion Cells
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Afferent Neurons
                Retinal Ganglion Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Ganglion Cells
                Retinal Ganglion Cells
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Ganglion Cells
                Retinal Ganglion Cells
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Dementia
                Alzheimer Disease
                Medicine and Health Sciences
                Neurology
                Dementia
                Alzheimer Disease
                Medicine and Health Sciences
                Neurology
                Neurodegenerative Diseases
                Alzheimer Disease
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Enzyme-Linked Immunoassays
                Research and Analysis Methods
                Database and Informatics Methods
                Health Informatics
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Mood Disorders
                Depression
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Growth Factors
                Nerve Growth Factor
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Nerve Growth Factor
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Nerve Growth Factor
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurochemicals
                Nerve Growth Factor
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurochemicals
                Nerve Growth Factor
                Medicine and Health Sciences
                Neurology
                Brain Diseases
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