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Molecular Mechanisms and Pathophysiology of Cerebral Ischemia

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 10909

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Special Issue Editor

Prof. Dr. Moo-Ho Won

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Guest Editor

Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea
Interests: ischemia/reperfusion; neurodegeneration; neurogenesis; cerebral ischemia; aging in CNS
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cerebral ischemia is the leading cause of death worldwide. Despite great efforts to develop potential treatments, the molecular and cellular mechanisms of cerebral ischemia are not fully understood.

Many researchers have been using various animal models of cerebral ischemia with different species of animals, different methods of occlusion of blood vessels, and different periods of occlusion time. The models of cerebral ischemia can be divided into focal and global models. Focal ischemia is characterized by a reduction of cerebral blood flow in a distinct region of the brain, whereas in global ischemia, the reduction of blood flow affects the entire brain or forebrain. Neuronal or tissue damage are different according to the type of ischemic insult. In animal models of global transient cerebral or forebrain ischemia, neuronal damage/death (loss) occurs in vulnerable regions of the brain (i.e., the hippocampus), whereas in animal models of transient focal brain ischemia, neuronal loss occurs when the ischemic duration (damage) is short (mild), or infarction (necrosis) occurs when the ischemic damage (duration) is severe (long). In this regard, the mechanisms of neuronal loss or infarction are apparently different according to the type of ischemic insult.

Diverse mechanisms of pathophysiological events in ischemic damage have been suggested, including the activation of glutamate receptors, a sustained increase in intracellular calcium, oxidative stress caused by free radicals, and the activation of resident microglia related to neuroinflammatory reactions. In addition, the dysfunction of cells related to the blood–brain barrier (BBB), including endothelial cells, astrocytes and pericytes, as well as microglia, is also suggested as a possible mechanism of ischemic injuries.

This Special Issue aims to study the control or modulation of diverse pathways during or after ischemic injuries at the molecular and cellular levels to prevent, attenuate or heal ischemia damage following various brain ischemic insults.

Prof. Dr. Moo-Ho Won
Guest Editor

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Keywords

transient or permanent ischemia
neuronal death
necrosis
inflammation
oxidative stress
cytotoxicity
blood-brain barrier
neuroprotection
therapeutic strategy

Published Papers (4 papers)

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Research

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19 pages, 10609 KiB

Open AccessArticle

Hypothermia Induced by Oxcarbazepine after Transient Forebrain Ischemia Exerts Therapeutic Neuroprotection through Transient Receptor Potential Vanilloid Type 1 and 4 in Gerbils

by Hyung-Il Kim, Jae-Chul Lee, Dae Won Kim, Myoung Cheol Shin, Jun Hwi Cho, Ji Hyeon Ahn, Soon-Sung Lim, Il Jun Kang, Joon Ha Park, Moo-Ho Won and Tae-Kyeong Lee

Int. J. Mol. Sci. 2022, 23(1), 237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010237 - 27 Dec 2021

Cited by 6 | Viewed by 2341

Abstract

In the present study, we investigated the neuroprotective effect of post-ischemic treatment with oxcarbazepine (OXC; an anticonvulsant compound) against ischemic injury induced by transient forebrain ischemia and its mechanisms in gerbils. Transient ischemia was induced in the forebrain by occlusion of both common carotid arteries for 5 min under normothermic conditions (37 ± 0.2 °C). The ischemic gerbils were treated with vehicle, hypothermia (whole-body cooling; 33.0 ± 0.2 °C), or 200 mg/kg OXC. Post-ischemic treatments with vehicle and hypothermia failed to attenuate and improve, respectively, ischemia-induced hyperactivity and cognitive impairment (decline in spatial and short-term memory). However, post-ischemic treatment with OXC significantly attenuated the hyperactivity and the cognitive impairment, showing that OXC treatment significantly reduced body temperature (to about 33 °C). When the hippocampus was histopathologically examined, pyramidal cells (principal neurons) were dead (lost) in the subfield Cornu Ammonis 1 (CA1) of the gerbils treated with vehicle and hypothermia on Day 4 after ischemia, but these cells were saved in the gerbils treated with OXC. In the gerbils treated with OXC after ischemia, the expression of transient receptor potential vanilloid type 1 (TRPV1; one of the transient receptor potential cation channels) was significantly increased in the CA1 region compared with that in the gerbils treated with vehicle and hypothermia. In brief, our results showed that OXC-induced hypothermia after transient forebrain ischemia effectively protected against ischemia–reperfusion injury through an increase in TRPV1 expression in the gerbil hippocampal CA1 region, indicating that TRPV1 is involved in OXC-induced hypothermia. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Ischemia)

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22 pages, 2369 KiB

Open AccessArticle

Differential Association of 4E-BP2-Interacting Proteins Is Related to Selective Delayed Neuronal Death after Ischemia

by Emma Martínez-Alonso, Natalia Guerra-Pérez, Alejandro Escobar-Peso, Ignacio Regidor, Jaime Masjuan and Alberto Alcázar

Int. J. Mol. Sci. 2021, 22(19), 10327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910327 - 25 Sep 2021

Cited by 3 | Viewed by 1906

Abstract

Cerebral ischemia induces an inhibition of protein synthesis and causes cell death and neuronal deficits. These deleterious effects do not occur in resilient areas of the brain, where protein synthesis is restored. In cellular stress conditions, as brain ischemia, translational repressors named eukaryotic initiation factor (eIF) 4E-binding proteins (4E-BPs) specifically bind to eIF4E and are critical in the translational control. We previously described that 4E-BP2 protein, highly expressed in brain, can be a molecular target for the control of cell death or survival in the reperfusion after ischemia in an animal model of transient cerebral ischemia. Since these previous studies showed that phosphorylation would not be the regulation that controls the binding of 4E-BP2 to eIF4E under ischemic stress, we decided to investigate the differential detection of 4E-BP2-interacting proteins in two brain regions with different vulnerability to ischemia-reperfusion (IR) in this animal model, to discover new potential 4E-BP2 modulators and biomarkers of cerebral ischemia. For this purpose, 4E-BP2 immunoprecipitates from the resistant cortical region and the vulnerable hippocampal cornu ammonis 1 (CA1) region were analyzed by two-dimensional (2-D) fluorescence difference in gel electrophoresis (DIGE), and after a biological variation analysis, 4E-BP2-interacting proteins were identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. Interestingly, among the 4E-BP2-interacting proteins identified, heat shock 70 kDa protein-8 (HSC70), dihydropyrimidinase-related protein-2 (DRP2), enolase-1, ubiquitin carboxyl-terminal hydrolase isozyme-L1 (UCHL1), adenylate kinase isoenzyme-1 (ADK1), nucleoside diphosphate kinase-A (NDKA), and Rho GDP-dissociation inhibitor-1 (Rho-GDI), were of notable interest, showing significant differences in their association with 4E-BP2 between resistant and vulnerable regions to ischemic stress. Our data contributes to the first characterization of the 4E-BP2 interactome, increasing the knowledge in the molecular basis of the protection and vulnerability of the ischemic regions and opens the way to detect new biomarkers and therapeutic targets for diagnosis and treatment of cerebral ischemia. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Ischemia)

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18 pages, 3859 KiB

Open AccessArticle

Ischemia-Reperfusion under Hyperthermia Increases Heme Oxygenase-1 in Pyramidal Neurons and Astrocytes with Accelerating Neuronal Loss in Gerbil Hippocampus

by Tae-Kyeong Lee, Jae-Chul Lee, Dae Won Kim, Bora Kim, Hyejin Sim, Jong Dai Kim, Ji Hyeon Ahn, Joon Ha Park, Choong-Hyun Lee, Moo-Ho Won and Soo Young Choi

Int. J. Mol. Sci. 2021, 22(8), 3963; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083963 - 12 Apr 2021

Cited by 6 | Viewed by 2039

Abstract

It has been studied that the damage or death of neurons in the hippocampus is different according to hippocampal subregions, cornu ammonis 1–3 (CA1–3), after transient ischemia in the forebrain, showing that pyramidal neurons located in the subfield CA1 (CA1) are most vulnerable to this ischemia. Hyperthermia is a proven risk factor for brain ischemia and can develop more severe and extensive brain damage related with mortality rate. It is well known that heme oxygenase-1 (HO-1) activity and expression is increased by various stimuli in the brain, including hyperthermia. HO-1 can be either protective or deleterious in the central nervous system, and its roles depend on the expression levels of enzymes. In this study, we investigated the effects of hyperthermia during ischemia on HO-1 expression and neuronal damage/death in the hippocampus to examine the relationship between HO-1 and neuronal damage/death following 5-min transient ischemia in the forebrain using gerbils. Gerbils were assigned to four groups: (1) sham-operated gerbils with normothermia (Normo + sham group); (2) ischemia-operated gerbils with normothermia (Normo + ischemia group); (3) sham-operated gerbils with hyperthermia (39.5 ± 0.2 °C) during ischemia (Hyper + sham group); and (4) ischemia-operated gerbils with hyperthermia during ischemia (Hyper + ischemia group). HO-1 expression levels in CA1–3 of the Hyper + ischemia group were significantly higher than those in the Normo + ischemia group. HO-1 immunoreactivity in the Hyper + ischemia group was significantly increased in pyramidal neurons and astrocytes with time after ischemia, and the immunoreactivity was significantly higher than that in the Normo + ischemia group. In the Normo + Ischemia group, neuronal death was shown in pyramidal neurons located only in CA1 at 5 days after ischemia. However, in the Hyper + ischemia group, pyramidal neuronal death occurred in CA1–3 at 2 days after ischemia. Taken together, our findings showed that brain ischemic insult during hyperthermic condition brings up earlier and severer neuronal damage/death in the hippocampus, showing that HO-1 expression in neurons and astrocytes is different according to brain subregions and temperature condition. Based on these findings, we suggest that hyperthermia in patients with ischemic stroke must be taken into the consideration in the therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Ischemia)

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Review

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22 pages, 1560 KiB

Open AccessReview

The Influence of Mitochondrial-DNA-Driven Inflammation Pathways on Macrophage Polarization: A New Perspective for Targeted Immunometabolic Therapy in Cerebral Ischemia-Reperfusion Injury

by Sihang Yu, Jiaying Fu, Jian Wang, Yuanxin Zhao, Buhan Liu, Jiahang Wei, Xiaoyu Yan and Jing Su

Int. J. Mol. Sci. 2022, 23(1), 135; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010135 - 23 Dec 2021

Cited by 11 | Viewed by 3695

Abstract

Cerebral ischemia-reperfusion injury is related to inflammation driven by free mitochondrial DNA. At the same time, the pro-inflammatory activation of macrophages, that is, polarization in the M1 direction, aggravates the cycle of inflammatory damage. They promote each other and eventually transform macrophages/microglia into neurotoxic macrophages by improving macrophage glycolysis, transforming arginine metabolism, and controlling fatty acid synthesis. Therefore, we propose targeting the mtDNA-driven inflammatory response while controlling the metabolic state of macrophages in brain tissue to reduce the possibility of cerebral ischemia-reperfusion injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Cerebral Ischemia)

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