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      Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment

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          Background and Purpose

          Memory impairment can be progressive in neurodegenerative diseases, and physiological ageing or brain injury, mitochondrial dysfunction and oxidative stress are critical components of these issues. An early clinical study has demonstrated cognitive improvement during erythropoietin treatment in patients with chronic renal failure. As erythropoietin cannot freely cross the blood–brain barrier, we tested EH-201 (2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside, also known as TSG), a low MW inducer of erythropoietin, for its therapeutic effects on memory impairment in models of neurodegenerative diseases, physiological ageing or brain injury.

          Experimental Approach

          The effects of EH-201 were investigated in astrocytes and PC12 neuronal-like cells. In vivo, we used sleep-deprived (SD) mice as a stress model, amyloid-β (Aβ)-injected mice as a physiological ageing model and kainic acid (KA)-injected mice as a brain damage model to assess the therapeutic effects of EH-201.

          Key Results

          EH-201 induced expression of erythropoietin, PPAR-γ coactivator 1α (PGC-1α) and haemoglobin in astrocytes and PC12 neuronal-like cells. In vivo, EH-201 treatment restored memory impairment, as assessed by the passive avoidance test, in SD, Aβ and KA mouse models. In the hippocampus of mice given EH-201 in their diet, levels of erythropoietin, PGC-1α and haemoglobin were increased

          Conclusions and Implications

          The induction of endogenous erythropoietin in neuronal cells by inducers such as EH-201 might be a therapeutic strategy for memory impairment in neurodegenerative disease, physiological ageing or traumatic brain injury.

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          Most cited references 59

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          The role of sleep in learning and memory.

           P Maquet (2001)
          Sleep has been implicated in the plastic cerebral changes that underlie learning and memory. Indications that sleep participates in the consolidation of fresh memory traces come from a wide range of experimental observations. At the network level, reactivations during sleep of neuronal assemblies recently challenged by new environmental circumstances have been reported in different experimental designs. These neuronal assemblies are proposed to be involved in the processing of memory traces during sleep. However, despite this rapidly growing body of experimental data, evidence for the influence of sleep discharge patterns on memory traces remains fragmentary. The underlying role of sleep in learning and memory has yet to be precisely characterized.
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            Mitochondria and neuronal activity.

            Mitochondria are central for various cellular processes that include ATP production, intracellular Ca(2+) signaling, and generation of reactive oxygen species. Neurons critically depend on mitochondrial function to establish membrane excitability and to execute the complex processes of neurotransmission and plasticity. While much information about mitochondrial properties is available from studies on isolated mitochondria and dissociated cell cultures, less is known about mitochondrial function in intact neurons in brain tissue. However, a detailed description of the interactions between mitochondrial function, energy metabolism, and neuronal activity is crucial for the understanding of the complex physiological behavior of neurons, as well as the pathophysiology of various neurological diseases. The combination of new fluorescence imaging techniques, electrophysiology, and brain slice preparations provides a powerful tool to study mitochondrial function during neuronal activity, with high spatiotemporal resolution. This review summarizes recent findings on mitochondrial Ca(2+) transport, mitochondrial membrane potential (DeltaPsi(m)), and energy metabolism during neuronal activity. We will first discuss interactions of these parameters for experimental stimulation conditions that can be related to the physiological range. We will then describe how mitochondrial and metabolic dysfunction develops during pathological neuronal activity, focusing on temporal lobe epilepsy and its experimental models. The aim is to illustrate that 1) the structure of the mitochondrial compartment is highly dynamic in neurons, 2) there is a fine-tuned coupling between neuronal activity and mitochondrial function, and 3) mitochondria are of central importance for the complex behavior of neurons.
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              Recombinant human erythropoietin in the treatment of acute ischemic stroke.

              Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40,000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

                Author and article information

                Br J Pharmacol
                Br. J. Pharmacol
                British Journal of Pharmacology
                Blackwell Publishing Ltd (Oxford, UK )
                October 2015
                10 August 2015
                : 172
                : 19
                : 4741-4756
                [1 ]Institute of Biopharmaceutical Sciences, National Yang-Ming University Taipei, Taiwan
                [2 ]Research Center for Drug Discovery, National Yang-Ming University Taipei, Taiwan
                [3 ]Research Center for Natural Products and Drug Development, Institute of Natural Products, Kaohsiung Medical University Kaohsiung, Taiwan
                Author notes
                Professor Rong-Tsun Wu, Institute of Biopharmaceutical Sciences, Research Center for Drug Discovery, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei 112 Taiwan. E-mail: rtwu@
                © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                Research Papers

                Pharmacology & Pharmaceutical medicine


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