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      Flavonoid Naringenin Attenuates Oxidative Stress, Apoptosis and Improves Neurotrophic Effects in the Diabetic Rat Retina

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          Abstract

          Diabetic retinopathy (DR) is one of the leading causes of decreased vision and blindness worldwide. Diabetes-induced oxidative stress is believed to be the key factor that initiates neuronal damage in the diabetic retina leading to DR. Experimental approaches to utilize dietary flavonoids, which possess both antidiabetic and antioxidant activities, might protect the retinal damage in diabetes. The aim of this study was to investigate the potential protective effects of naringenin in the retina of streptozotocin-induced diabetic rats. Diabetic rats were orally treated and untreated with naringenin (50 mg/kg/day) for five weeks and retinas were analyzed for markers of oxidative stress, apoptosis and neurotrophic factors. Systemic effects of naringenin treatments were also analyzed and compared with untreated groups. The results showed that elevated levels of thiobarbituric acid reactive substances (TBARs) and decreased level of glutathione (GSH) in diabetic rats were ameliorated with naringenin treatments. Moreover, decreased levels of neuroprotective factors (Brain derived neurotrophic factor (BDNF)), tropomyosin related kinase B (TrkB) and synaptophysin in diabetic retina were augmented with naringenin treatments. In addition, naringenin treatment ameliorated the levels of apoptosis regulatory proteins; B cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax) and caspase-3 in the diabetic retina. Thus, the study demonstrates the beneficial effects of naringenin that possesses anti-diabetic, antioxidant and antiapoptotic properties, which may limit neurodegeneration by providing neurotrophic support to prevent retinal damage in diabetic retinopathy.

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          Most cited references40

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          Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease.

          Brain-derived neurotrophic factor (BDNF) is a prototypic neurotrophin that regulates diverse developmental events from the selection of neural progenitors to the terminal dendritic differentiation and connectivity of neurons. We focus here on activity-dependent synaptic regulation by BDNF and its receptor, full length TrkB. BDNF-TrkB signaling is involved in transcription, translation, and trafficking of proteins during various phases of synaptic development and has been implicated in several forms of synaptic plasticity. These functions are carried out by a combination of the three signaling cascades triggered when BDNF binds TrkB: The mitogen-activated protein kinase (MAPK), the phospholipase Cgamma (PLC PLCgamma), and the phosphatidylinositol 3-kinase (PI3K) pathways. MAPK and PI3K play crucial roles in both translation and/or trafficking of proteins induced by synaptic activity, whereas PLCgamma regulates intracellular Ca(2+) that can drive transcription via cyclic AMP and a protein kinase C. Conversely, the abnormal regulation of BDNF is implicated in various developmental and neurodegenerative diseases that perturb neural development and function. We will discuss the current state of understanding BDNF signaling in the context of synaptic development and plasticity with a focus on the postsynaptic cell and close with the evidence that basic mechanisms of BDNF function still need to be understood to effectively treat genetic disruptions of these pathways that cause devastating neurodevelopmental diseases.
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            Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons.

            Despite being the most abundant synaptic vesicle membrane protein, the function of synaptophysin remains enigmatic. For example, synaptic transmission was reported to be completely normal in synaptophysin knockout mice; however, direct experiments to monitor the synaptic vesicle cycle have not been carried out. Here, using optical imaging and electrophysiological experiments, we demonstrate that synaptophysin is required for kinetically efficient endocytosis of synaptic vesicles in cultured hippocampal neurons. Truncation analysis revealed that distinct structural elements of synaptophysin differentially regulate vesicle retrieval during and after stimulation. Thus, synaptophysin regulates at least two phases of endocytosis to ensure vesicle availability during and after sustained neuronal activity. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Neuroprotective effect of naringenin is mediated through suppression of NF-κB signaling pathway in experimental stroke.

              Oxidative stress and inflammation play an integral role in the pathogenesis of cerebral ischemia that leads to a cascade of events culminating in the death of neurons and their supporting structures. The signaling pathways that link these events are not fully understood. Recent studies have demonstrated a close link between the nuclear factor-κB (NF-κB) signaling pathway and cerebral ischemia/reperfusion (I/R)-induced inflammation. Flavonoids have been suggested to exert human health benefits by anti-oxidant and anti-inflammatory mechanisms. In this study we undertook a pharmacological approach to investigate the ability of naringenin, a potent flavonoid, to prevent oxidative stress and NF-κB-mediated inflammatory brain damage in the rat model of focal cerebral I/R injury. To test this hypothesis, male Wistar rats were pretreated with naringenin once daily for 21 days and then subjected to 1h of middle cerebral artery occlusion followed by 23 h of reperfusion. Naringenin treatment successfully upregulates the antioxidant status, decreases the infarct size and lowers the levels of myeloperoxidase, nitric oxide and cytokines, besides functional recovery returned close to the baseline. Moreover, immunohistochemical and Western blot analyses clearly demonstrated that naringenin treatment limits glial activation and downregulates the NF-κB expression level and their target genes. These results show, prophylactic treatment with naringenin improved functional outcomes and abrogated the ischemic brain injury by suppressing NF-κB-mediated neuroinflammation. The present study suggests that naringenin may be used as a potential neuroprotectant in patients at high risk of ischemic stroke. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                24 October 2017
                October 2017
                : 9
                : 10
                : 1161
                Affiliations
                [1 ]Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; Dalia.ib89@ 123456gmail.com (D.I.A.-D.); alhomida@ 123456ksu.edu.sa (A.S.A.)
                [2 ]Department of Pharmacology &Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; mmahmedd@ 123456ksu.edu.sa (M.M.A.); rejaie@ 123456ksu.edu.sa (S.S.A.-R.)
                Author notes
                [* ]Correspondence: mola@ 123456ksu.edu.sa or shamsulola@ 123456gmail.com ; Tel.: +966-558013579
                Article
                nutrients-09-01161
                10.3390/nu9101161
                5691777
                29064407
                46e26eef-68d9-4255-b48c-e63c29b9f42e
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 September 2017
                : 13 October 2017
                Categories
                Article

                Nutrition & Dietetics
                diabetic retinopathy,flavonoid,naringenin,neurotrophic factor,oxidative stress,apoptosis

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