Abstract
Aims: To compare the neuroprotection of erythropoietin (EPO) and EPO fusion protein containing transduction domain derived from HIV TAT (EPO-TAT) against ischemic brain injury, inclusive of the side effect, and explore the mechanism underlying the role of EPO-TAT in a transient focal cerebral ischemia model in rats.
Methods: Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. Rats were treated, respectively, with following regimens: saline, 1000 U/kg EPO, 5000 U/kg EPO, 1000 U/kg EPO-TAT, 1000 U/kg EPOTAT + 5 µl of 10 mM LY294002 (or/plus 5 µl of 5 mM PD98059). Neurological deficit scores, infarct volume, and hematologic side effect were assessed at 72 hours after MCAO. Apoptotic cells were determined with TUNEL staining. The expression and localization of phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) were detected with Western blot, immunohistochemistry, and immunofluorescence, respectively.
Results: 1000 U/kg EPO-TAT exhibited a comparable neuroprotection to 5000 U/kg EPO, as evidenced by a comparable attenuation in neurological deficit, infarct volume, and number of apoptotic cells in the rat ischemic cortex after MCAO. The pAKT and pERK levels were significantly elevated solely in neurons of rodents receiving EPO or EPO-TAT treatments, suggesting the concurrent activation of these two pathways. Specific inhibition of either AKT or ERK pathway partially abolished EPO-TAT protection, but exhibited no influence on the activation status of its counterpart, suggesting no cross-modulation between these two protective pathways.
Conclusion: Our study indicates that EPO-TAT at 1000 U/kg displays neuroprotection with no detectable side effects. The mechanism for neuroprotection may be attributable to the simultaneous activation of the AKT and ERK pathways, which preserve neuronal cell viability and attenuate behavioral deficits.
Keywords: Cerebral ischemia, erythropoietin, neurodegeneration, neuroprotection, reperfusion.
CNS & Neurological Disorders - Drug Targets
Title:The Neuroprotective Mechanism of Erythropoietin-TAT Fusion Protein Against Neurodegeneration from Ischemic Brain Injury
Volume: 13 Issue: 8
Author(s): Ping Liu, Xiaolei Liu, Anthony Kian-Fong Liou, Juan Xing, Zheng Jing, Xunming Ji, Xiangrong Liu, Haiping Zhao, Feng Yan, Jun Chen, Guodong Cao and Yumin Luo
Affiliation:
Keywords: Cerebral ischemia, erythropoietin, neurodegeneration, neuroprotection, reperfusion.
Abstract: Aims: To compare the neuroprotection of erythropoietin (EPO) and EPO fusion protein containing transduction domain derived from HIV TAT (EPO-TAT) against ischemic brain injury, inclusive of the side effect, and explore the mechanism underlying the role of EPO-TAT in a transient focal cerebral ischemia model in rats.
Methods: Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. Rats were treated, respectively, with following regimens: saline, 1000 U/kg EPO, 5000 U/kg EPO, 1000 U/kg EPO-TAT, 1000 U/kg EPOTAT + 5 µl of 10 mM LY294002 (or/plus 5 µl of 5 mM PD98059). Neurological deficit scores, infarct volume, and hematologic side effect were assessed at 72 hours after MCAO. Apoptotic cells were determined with TUNEL staining. The expression and localization of phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) were detected with Western blot, immunohistochemistry, and immunofluorescence, respectively.
Results: 1000 U/kg EPO-TAT exhibited a comparable neuroprotection to 5000 U/kg EPO, as evidenced by a comparable attenuation in neurological deficit, infarct volume, and number of apoptotic cells in the rat ischemic cortex after MCAO. The pAKT and pERK levels were significantly elevated solely in neurons of rodents receiving EPO or EPO-TAT treatments, suggesting the concurrent activation of these two pathways. Specific inhibition of either AKT or ERK pathway partially abolished EPO-TAT protection, but exhibited no influence on the activation status of its counterpart, suggesting no cross-modulation between these two protective pathways.
Conclusion: Our study indicates that EPO-TAT at 1000 U/kg displays neuroprotection with no detectable side effects. The mechanism for neuroprotection may be attributable to the simultaneous activation of the AKT and ERK pathways, which preserve neuronal cell viability and attenuate behavioral deficits.
Export Options
About this article
Cite this article as:
Liu Ping, Liu Xiaolei, Liou Kian-Fong Anthony, Xing Juan, Jing Zheng, Ji Xunming, Liu Xiangrong, Zhao Haiping, Yan Feng, Chen Jun, Cao Guodong and Luo Yumin, The Neuroprotective Mechanism of Erythropoietin-TAT Fusion Protein Against Neurodegeneration from Ischemic Brain Injury, CNS & Neurological Disorders - Drug Targets 2014; 13 (8) . https://dx.doi.org/10.2174/1871527313666140806155259
DOI https://dx.doi.org/10.2174/1871527313666140806155259 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Effects of Novel Monoamine Oxidases and Cholinesterases Targeting Compounds on Brain Neurotransmitters and Behavior in Rat Model of Vascular Dementia
Current Pharmaceutical Design Advances in the Chemistry of Saccharins: From Synthetic Novelties Towards Biologically Active Compounds
Current Medicinal Chemistry Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition
Current Medicinal Chemistry Nitric Oxide, Peroxynitrite, Peroxynitrous Acid, Nitroxyl, Nitrogen Dioxide, Nitrous Oxide: Biochemical Mechanisms and Bioaction
Current Bioactive Compounds PEDF & Stem Cells: Niche vs. Nurture
Current Drug Delivery Leukocyte-Endothelial Cell Interactions: A Therapeutic Target to Ameliorate Inflammatory Diseases
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Anderson-Fabry Disease in Children
Current Pharmaceutical Design Brain Segmentation Using Deep Neural Networks
International Journal of Sensors, Wireless Communications and Control Nitric Oxide and Inflammation
Inflammation & Allergy - Drug Targets (Discontinued) FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment
Current Medicinal Chemistry Neurotrophic Factors for Retinal Ganglion Cell Neuropathy - With a Special Reference to Diabetic Neuropathy in the Retina
Current Diabetes Reviews Therapeutic Advances in the Treatment of Alzheimer's Disease: Present and Future
Current Drug Therapy Intracompartmental Delivery of CNTF as Therapy for Huntingtons Disease and Retinitis Pigmentosa
Current Gene Therapy Current Directions in Non-Invasive Low Intensity Electric Brain Stimulation for Depressive Disorder
CNS & Neurological Disorders - Drug Targets Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential
Current Topics in Medicinal Chemistry Combined Ischemic Preconditioning and Resveratrol Improved Bloodbrain Barrier Breakdown <i>via</i> Hippo/YAP/TAZ Signaling Pathway
CNS & Neurological Disorders - Drug Targets Therapeutic Effects of Rivastigmine and Alfa-Lipoic Acid Combination in the Charles Bonnet Syndrome: Electroencephalography Correlates
Current Clinical Pharmacology New Development and Application of Ultrasound Targeted Microbubble Destruction in Gene Therapy and Drug Delivery
Current Gene Therapy Inhibition of the Function of TRPV1-Expressing Nociceptive Sensory Neurons by Somatostatin 4 Receptor Agonism: echanism and Therapeutical Implications
Current Topics in Medicinal Chemistry Gene Elements that Regulate Streptococcus pneumoniae Virulence and Immunity Evasion
Current Gene Therapy