AUCTORES
Globalize your Research
Research Article | DOI: https://doi.org/10.31579/2578-8868/228
1 Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China.
2 Department of Anesthesiology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
3 Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China.
4 Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China
*Corresponding Author: Yanhui Cai, Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China and Yulong Ma, Department of Anesthesiology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
Citation: Doutong Yu, Yuting Qiao, Haiyun Guo, Zejun Gao, Li Guo. et all (2022). Astrocytic Glycogen Mobilization in Cerebral Ischemia/Reperfusion Injury. J. Neuroscience and Neurological Surgery. 11(3); DOI:10.31579/2578-8868/228
Copyright: © 2022 Yanhui Cai, Yulong Ma, 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
Received: 31 December 2021 | Accepted: 28 January 2022 | Published: 03 February 2022
Keywords: ischemia/reperfusion injury; astrocyte; glycogen; neuroprotection
Glycogen is an important energy reserve in the brain and can be rapidly degraded to maintain metabolic homeostasis during cerebral blood vessel occlusion. Recent studies have pointed out the alterations in glycogen and its underlying mechanism during reperfusion after ischemic stroke. In addition, glycogen metabolism may work as a promising therapeutic target to relieve reperfusion injury. Here, we summarize the progress of glycogen metabolism during reperfusion injury and its corresponding application in patients suffering from ischemic stroke.
Ischemic stroke is the second leading cause of death in the world, and vascular recanalization by thrombolysis is the main treatment method at present, but thrombolysis can cause reperfusion injury. [1] The main mechanisms of reperfusion injury include glutamate poisoning, excess oxygen free radicals, inflammation and calcium overload. The deficiency and restoration of blood flow during ischemia/reperfusion (I/R) can disrupt energy balance in the brain, which can aggravate the disruption of brain homeostasis. Accordingly, it is crucial to uncover the alterations in energy metabolism and metabolic disorders during I/R.
In the central nervous system, astrocytes account for 20%-24% of the total number of cells, and their number even exceeds that during neurological diseases, such as ischemia. [2] As a prior target for the neuroprotection of ischemic stroke, astrocytes contact, interact with and affect all parenchymal cells. [3, 4] Cerebral ischemia affects all cellular components in the brain and initiates signaling responses between similar and different types of cells. [5]
Astrocytes play important roles in the brain, including neurotransmitter absorption and secretion, and they maintain the blood–brain barrier by providing biochemical support to the endothelial cells of the blood–brain barrier. Astrocytes provide nutrients to the nervous tissues to maintain the balance of extracellular ions and play a role in the repair processes following head and spinal cord trauma and scar formation. [6] Glycogen is found mainly in astrocytes but not in neurons. When the brain is ischemic, astrocytes located near neurons in the frontal cortex and hippocampus supply these neurons with glucose. [7] Glycogen, a high polymer of glucose, accumulates in astrocytes during ischemia–reperfusion, mainly because of impaired glycogen decomposition. Based on these findings, there is a protective effect of glycogen decomposition on neurons. [8] This project mainly discusses the role and mechanism of astrocyte glycogen metabolism in cerebral ischemia–reperfusion injury.
Glycogen is the stored form of glucose in cells. Glycogen is a high molecular compound of glucose and is the second largest energy reserve in the human body behind fat, which mainly exists in astrocytes. Brain glycogen, as an important endogenous energy substance in the brain, mainly exists in astrocytes and is rapidly decomposed to provide additional energy support for the brain when blood vessels are blocked. [9] As an important energy source for astrocytes, glycogen is a regulator of astrocyte utilization of blood-borne glucose. [10, 11] During brain stimulation, glycogen decomposition could meet the energy requirements by inhibiting astrocyte hexokinase and glycogen decomposition promotes glutamate resynthesis in astrocytes by astrocyte utilization of extracellular and blood-derived grapes. [10, 12] Pyruvate is produced by astrocyte glycogen and can achieve aerobic metabolism by traveling to neurons and providing energy for neuronal plasticity. Meanwhile, the dehydration of the glycogen carbon can be produced through the carboxylation of pyruvate to produce glutamate. [13-16]
Ischemic stroke is a disease with a high incidence and fatality rate. Because of the reduced blood flow and lowered oxygen and glucose levels in the brain, cerebral ischemia causes neuronal injury or death in part of the brain, and the common cause of damage is hemisphere contralateral hemiplegia. Ischemic stroke causes problems for patients. For example, patients have difficulty moving without assistance. Hundreds of patients cannot spend their time as they wish, and some patients even suffer from permanent disease. [17-19]
Cerebral ischemia affects all cellular components of the brain and induces signaling responses between cells of the same and between different types of cells. [20] Glycogen release in astrocytes can isolate excessive release of extracellular K+ from the nerve. [21] The expression and activity of enzymes involved in glycogen metabolism have been shown to be induced by the vasoconstrictor endothelin-1 in rats with ischemic stroke. At 6 and 24 h, the level of glycogen in the ipsilateral cerebral hemisphere was elevated relative to the contralateral cerebral hemisphere (25% and 39%, respectively), and there was a similarity in glycogen synthase activity and glycogen branching enzyme expression between the ipsilateral, contralateral and pseudocontrol hemispheres. The activity of rate-limiting enzyme involved in glycogen decomposition and glycogen phosphorylase decreased by 58$ h after stroke, and the activity of camp-dependent protein kinase A (PKA) was reduced by 48% in the same way. At 24 h after stroke, the rate of glycogen debranching enzyme expression was reduced by 77% and 72% at the protein and mRNA levels, respectively. [22] Hypoxia and inhibition of PKA activity significantly decreased glycogen phosphorylase activity and increased glycogen accumulation but did not change glycogen synthase activity. In addition, elevated glycogen levels provide metabolic support for astrocytes during periods of hypoxia. [22] During ischemic stroke, mitochondria in astrocytes can store a large amount of glycogen. Glycogen is more resilient and adaptable in a hypoxic environment to provide energy support for damaged neurons through their own biological systems and changes in mitochondrial dynamics. At the same time, as a bridge between the neural network and the vascular network, AS can regulate cerebral blood flow by contacting the arterioles and capillaries of the central nerve system to affect the diameter of blood vessels. [23]
Ischemia–reperfusion is designed to save penumbra tissue and reduce infarct size. The deficiency and restoration of blood flow disrupt the balance of brain energy and lead to injury during ischemic reperfusion. The common symptoms are glutamate poisoning, oxygen free radical overload, inflammation, and calcium overload. Recanalization of obstructed energy metabolism in the bloodstream can aggravate ischemia reperfusion injury. The loss of blood disrupts the brain's energy balance. Brain glycogen, which is rapidly decomposing, provides extra energy for the brain during blood vessel blockage. After glycogen breaks down, glucose-6-phosphate can be generated through glycolysis to generate lactic acid for aerobic oxidation. On the other hand, after gluconeogenesis, glucose reduces the amount of oxygen concentration in cells by NADPH and glutathione generated through pentose phosphate. [24] Cerebral ischemia leads to A1 (injury)/A2 (protection) differentiation of astrocytes. [8] NF-kb is a key molecule of A1; likewise, STAT3 is a key molecule of A2. Peripheral studies suggest that ROS can activate NF-KB and inhibit STAT3. Glycogen catabolism, mediated by the PKA-PHK-GP signaling pathway, is the main cause of glycogen accumulation in reperfusion and promoting the decomposition of glycogen can play a protective role. Post ischemia–reperfusion injury can inhibit A1 formation and elevate A2 activation. [8] (Figure 1).
Glycogen mobilization could reduce ROS levels and further inhibit the NF-KB signaling circuit and activate the STAT3 signaling circuit to play a neuroprotective role. [25] Astrocytes fill up the space of damaged nerve cells in the central nervous system to form nerve scarring with keratin and possibly aiding in nerve repair, and gene ablation studies have shown that astrocytes do play an integral role in regeneration. [26]
Immunofluorescence staining of glycogen phosphorylase is a key enzyme of astrocyte-specific glycogen catabolism. Immunofluorescence staining confirms that glycogen phosphorylase content is increased in overexpressed gene mice with significantly reduced infarction, and significantly improved limb sensory and motor functions. [27]
There is a protective effect of elevated glucose transporter (GLUT) activity on cells during ischemic energy depletion. In addition, under physiological conditions, cultured astrocytes express GLUT1 and GLUT3 at low levels. Under physiological conditions, cultured astrocytes promoted the percent conversion of the transcription factor nuclear factor-JB (NF-JB) and increased GLUT3 expression under ischemic stress. Astrocyte GLUT3 improves resistance in response to fatal ischemic stress by increasing intracellular glucose storage during reperfusion. [28] Under pathological conditions, glycogen levels and metabolism could be influenced in cancer studies (gastric adenocarcinoma) and neurological diseases (Alzheimer's disease). [29-32]
Astrocyte glycogenolysis and lactic acid play a key role in memory formation, and astrocytic B2 adrenergic receptor and lactate can enhance memory. Glycogen decomposition plays an important role in memory and astrocyte-neuronal metabolic coupling primarily at the peak of brain development could meet energy requirements. [33]
Obviously, the aggregate formation of glycogen is the cause of epilepsy. In epilepsy studies with Lafora disease as an example, in an LD animal model, glycogen aggregates gathered into polyglucosan bodies, which are called Lafora bodies (LBs), suggesting that the elimination of glycogen synthase (GS) prevented the formation of LBs and the development of LDs. This also suggests that glycogen accumulation is the basis of the disease and related symptoms, further revealing the relationship between glycogen accumulation and seizures. [34] Meanwhile, this confirms that glycogen deficiency can reduce the occurrence of epilepsy. [34]
In ischemic rats, the deletion of CDK5 in astrocytes resulted in the recovery of motor function, the increase in perivascular endogenous astrocyte branches and endothelial PECAM1 and proliferation markers, and it also restored the blood–brain barrier and secretion of BDNF through endogenous astrocytes in ischemic rats. [35]
Ganglioside GM1 can increase glucose intake and mobilize glycogen storage. Additionally, it can stimulate the secretion of lactic acid from astrocytes and enhance the gene expression of PTG, hexokinase, Na+/K+ ATPASE α2 subunit, pyruvate dehydrogenase and transaldolase. The metabolic and neuroprotective roles of astrocytes were further identified and confirmed in brain diseases, such as spinal cord injury, Huntington's disease and Parkinson's disease. [36]
In chronic pain, lactic acid promotes astrocyte proliferation and reactive astrocyte proliferation through a common intracellular signaling pathway that promotes synaptic activity in the central nervous system, possibly due to the activity-dependent release of astrocytes to maintain continuously elevated extracellular lactic acid levels. Lactic acid has lasting effects on astrocytes and neurons mediated by extracellular receptor binding. [37] Apparently, the pathology of the central nervous system is often associated with reactive astrocyte hyperplasia accompanied by changes in the release of some neuroregulatory substances. Additionally, astrocytes are involved. [38]
In general, astrocyte glycogen is dynamic and active, and glycogen mobilization plays an integral role in neuronal development. In addition to changes in the physiological environment, for example, I/R, the dynamic changes, decomposition, accumulation and alienation of astrocyte glycogen are not negligible. At the same time, astrocyte glycogen is regarded as a new therapeutic target and has attracted much attention in the fields of nervous system diseases, cancer, and pain. The role and mechanism of astrocyte glycogen mobilization in other fields deserves further investigation and attention.
This study was financially supported by the National Natural Science Foundation of China (nos. 82001384 and 81901079).
Not applicable.
The datasets generated during the current study are available from the corresponding author upon reasonable request.
The authors declare no conflict of interest.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
