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Molecular and Cellular Mechanisms of Cerebral Ischemia
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Molecular and Cellular Mechanisms of Cerebral Ischemia

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 51351

Special Issue Editor

Prof. Dr. Moo-Ho Won

E-Mail Website
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 treatment, molecular, and cellular mechanisms of cerebral ischemia are not fully understood.

So far, 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. 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 kinds of ischemic insults. In animal models of global transient cerebral or forebrain ischemia, neuronal damage/death (loss) occurs in vulnerable regions of the brain (i.e., hippocampus), whereas in animal models of transient focal bran ischemia, neuronal loss occurs when ischemic duration (damage) is short (mild), or infarction (necrosis) occurs when ischemic damage (duration) is severe (long). In this regard, mechanisms of the neuronal loss or infarction are apparently different according to kinds of ischemic insults. 

Diverse mechanisms of pathophysiological events of ischemic damages have been suggested, including activation of glutamate receptors, sustained increase in intracellular calcium, oxidative stress caused by free radicals, and activation of resident microglia related to neuroinflammatory reaction. In addition, dysfunction of the 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 in molecular and cellular levels to prevent, attenuate or heal ischemia damages following various brain ischemic insults.

Prof. Dr. Moo-Ho Won
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Related Special Issue

Published Papers (10 papers)

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Research

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19 pages, 22194 KiB  
Article
Neuronal Death in the CNS Autonomic Control Center Comes Very Early after Cardiac Arrest and Is Not Significantly Attenuated by Prompt Hypothermic Treatment in Rats
by Ji Hyeon Ahn, Tae-Kyeong Lee, Hyun-Jin Tae, Bora Kim, Hyejin Sim, Jae-Chul Lee, Dae Won Kim, Yoon Sung Kim, Myoung Cheol Shin, Yoonsoo Park, Jun Hwi Cho, Joon Ha Park, Choong-Hyun Lee, Soo Young Choi and Moo-Ho Won
Cells 2021, 10(1), 60; https://doi.org/10.3390/cells10010060 - 2 Jan 2021
Cited by 4 | Viewed by 2441
Abstract
Autonomic dysfunction in the central nervous system (CNS) can cause death after recovery from a cardiac arrest (CA). However, few studies on histopathological changes in animal models of CA have been reported. In this study, we investigated the prevalence of neuronal death and [...] Read more.
Autonomic dysfunction in the central nervous system (CNS) can cause death after recovery from a cardiac arrest (CA). However, few studies on histopathological changes in animal models of CA have been reported. In this study, we investigated the prevalence of neuronal death and damage in various brain regions and the spinal cord at early times after asphyxial CA and we studied the relationship between the mortality rate and neuronal damage following hypothermic treatment after CA. Rats were subjected to 7–8 min of asphyxial CA, followed by resuscitation and prompt hypothermic treatment. Eight regions related to autonomic control (the cingulate cortex, hippocampus, thalamus, hypothalamus, myelencephalon, and spinal cord) were examined using cresyl violet (a marker for Nissl substance) and Fluoro-Jade B (a marker for neuronal death). The survival rate was 44.5% 1 day post-CA, 18.2% 2 days post-CA and 0% 5 days post-CA. Neuronal death started 12 h post-CA in the gigantocellular reticular nucleus and caudoventrolateral reticular nucleus in the myelencephalon and lamina VII in the cervical, thoracic, lumbar, and sacral spinal cord, of which neurons are related to autonomic lower motor neurons. In these regions, Iba-1 immunoreactivity indicating microglial activation (microgliosis) was gradually increased with time after CA. Prompt hypothermic treatment increased the survival rate at 5 days after CA with an attenuation of neuronal damages and death in the damaged regions. However, the survival rate was 0% at 12 days after CA. Taken together, our study suggests that the early damage and death of neurons related to autonomic lower motor neurons was significantly related to the high mortality rate after CA and that prompt hypothermic therapy could increase the survival rate temporarily after CA, but could not ultimately save the animal. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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17 pages, 2615 KiB  
Article
Ablation of Vitamin D Signaling Compromises Cerebrovascular Adaptation to Carotid Artery Occlusion in Mice
by Éva Pál, László Hricisák, Ágnes Lékai, Dorina Nagy, Ágnes Fülöp, Reinhold G. Erben, Szabolcs Várbíró, Péter Sándor and Zoltán Benyó
Cells 2020, 9(6), 1457; https://doi.org/10.3390/cells9061457 - 12 Jun 2020
Cited by 9 | Viewed by 2428
Abstract
Vitamin D insufficiency has been associated with increased incidence and severity of cerebrovascular disorders. We analyzed the impact of impaired vitamin D signaling on the anatomical and functional aspects of cerebrovascular adaptation to unilateral carotid artery occlusion (CAO), a common consequence of atherosclerosis [...] Read more.
Vitamin D insufficiency has been associated with increased incidence and severity of cerebrovascular disorders. We analyzed the impact of impaired vitamin D signaling on the anatomical and functional aspects of cerebrovascular adaptation to unilateral carotid artery occlusion (CAO), a common consequence of atherosclerosis and cause of ischemic stroke. Cerebrocortical blood flow (CoBF) showed a significantly increased drop and delayed recovery after CAO in mice carrying a functionally inactive vitamin D receptor (VDR) with the most sustained perfusion deficit in the temporal cortex. To identify the cause(s) for this altered adaptation, the extent of compensatory blood flow increase in the contralateral carotid artery and the morphology of pial collaterals between the anterior and middle cerebral arteries were determined. Whereas VDR deficiency had no significant influence on the contralateral carotid arterial blood flow increase, it was associated with decreased number and increased tortuosity of pial anastomoses resulting in unfavorable changes of the intracranial collateral circulation. These results indicate that VDR deficiency compromises the cerebrovascular adaptation to CAO with the most sustained consequences in the temporal cortex. The dysregulation can be attributed to the altered development and function of pial collateral circulation whereas extracranial vessels may not be impaired. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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18 pages, 4960 KiB  
Article
Lysophosphatidic Acid Receptor 5 Plays a Pathogenic Role in Brain Damage after Focal Cerebral Ischemia by Modulating Neuroinflammatory Responses
by Arjun Sapkota, Chi-Ho Lee, Se Jin Park and Ji Woong Choi
Cells 2020, 9(6), 1446; https://doi.org/10.3390/cells9061446 - 10 Jun 2020
Cited by 19 | Viewed by 3028
Abstract
Receptor-mediated lysophosphatidic acid (LPA) signaling has come to be considered an important event for various diseases. In cerebral ischemia, LPA1 has recently been identified as a receptor subtype that mediates brain injury, but the roles of other LPA receptor subtypes remain unknown. [...] Read more.
Receptor-mediated lysophosphatidic acid (LPA) signaling has come to be considered an important event for various diseases. In cerebral ischemia, LPA1 has recently been identified as a receptor subtype that mediates brain injury, but the roles of other LPA receptor subtypes remain unknown. Here, we investigated the potential role of LPA5 as a novel pathogenic factor for cerebral ischemia using a mouse model of transient middle cerebral artery occlusion (tMCAO). LPA5 was upregulated in the ischemic core region after tMCAO challenge, particularly in activated microglia. When TCLPA5, a selective LPA5 antagonist, was given to tMCAO-challenged mice immediately after reperfusion, brain damage, including brain infarction, functional neurological deficit, and neuronal and non-neuronal apoptosis, was reduced in mice. Similarly, delayed TCLPA5 administration (at three hours after reperfusion) reduced brain infarction and neurological deficit. The histological results demonstrated that TCLPA5 administration attenuated microglial activation, as evidenced by the decreased Iba1 immunoreactivities, the number of amoeboid cells, and proliferation in an injured brain. TCLPA5 administration also attenuated the upregulation of the expression of pro-inflammatory cytokines at mRNA levels in post-ischemic brain, which was also observed in lipopolysaccharide-stimulated BV2 microglia upon LPA5 knockdown. Overall, this study identifies LPA5 as a novel pathogenic factor for cerebral ischemia, further implicating it as a promising target for drug development to treat this disease. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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27 pages, 6189 KiB  
Article
Early Reperfusion Following Ischemic Stroke Provides Beneficial Effects, Even After Lethal Ischemia with Mature Neural Cell Death
by Yasue Tanaka, Nami Nakagomi, Nobutaka Doe, Akiko Nakano-Doi, Toshinori Sawano, Toshinori Takagi, Tomohiro Matsuyama, Shinichi Yoshimura and Takayuki Nakagomi
Cells 2020, 9(6), 1374; https://doi.org/10.3390/cells9061374 - 1 Jun 2020
Cited by 21 | Viewed by 4127
Abstract
Ischemic stroke is a critical disease caused by cerebral artery occlusion in the central nervous system (CNS). Recent therapeutic advances, such as neuroendovascular intervention and thrombolytic therapy, have allowed recanalization of occluded brain arteries in an increasing number of stroke patients. Although previous [...] Read more.
Ischemic stroke is a critical disease caused by cerebral artery occlusion in the central nervous system (CNS). Recent therapeutic advances, such as neuroendovascular intervention and thrombolytic therapy, have allowed recanalization of occluded brain arteries in an increasing number of stroke patients. Although previous studies have focused on rescuing neural cells that still survive despite decreased blood flow, expanding the therapeutic time window may allow more patients to undergo reperfusion in the near future, even after lethal ischemia, which is characterized by death of mature neural cells, such as neurons and glia. However, it remains unclear whether early reperfusion following lethal ischemia results in positive outcomes. The present study used two ischemic mouse models—90-min transient middle cerebral artery occlusion (t-MCAO) paired with reperfusion to induce lethal ischemia and permanent middle cerebral artery occlusion (p-MCAO)—to investigate the effect of early reperfusion up to 8 w following MCAO. Although early reperfusion following 90-min t-MCAO did not rescue mature neural cells, it preserved the vascular cells within the ischemic areas at 1 d following 90-min t-MCAO compared to that following p-MCAO. In addition, early reperfusion facilitated the healing processes, including not only vascular but also neural repair, during acute and chronic periods and improved recovery. Furthermore, compared with p-MCAO, early reperfusion after t-MCAO prevented behavioral symptoms of neurological deficits without increasing negative complications, including hemorrhagic transformation and mortality. These results indicate that early reperfusion provides beneficial effects presumably via cytoprotective and regenerative mechanisms in the CNS, suggesting that it may be useful for stroke patients that experienced lethal ischemia. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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16 pages, 3001 KiB  
Article
Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke
by Shih-Yi Lin, Ya-Yu Wang, Cheng-Yi Chang, Chih-Cheng Wu, Wen-Ying Chen, Yu-Hsiang Kuan, Su-Lan Liao and Chun-Jung Chen
Cells 2020, 9(6), 1373; https://doi.org/10.3390/cells9061373 - 1 Jun 2020
Cited by 25 | Viewed by 2989
Abstract
Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective β-adrenoreceptor antagonist propranolol on [...] Read more.
Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective β-adrenoreceptor antagonist propranolol on hyperglycemia, inflammation, and brain injury in a rat model experiencing cerebral ischemia. Pretreatment with propranolol protected against postischemic brain infarction, edema, and apoptosis. The neuroprotection caused by propranolol was accompanied by a reduction in fasting glucose, fasting insulin, glucose tolerance impairment, plasma C-reactive protein, plasma free fatty acids, plasma corticosterone, brain oxidative stress, and brain inflammation. Pretreatment with insulin alleviated—while glucose augmented—postischemic brain injury and inflammation. Additionally, the impairment of insulin signaling in the gastrocnemius muscles was noted in rats with cerebral ischemia, with propranolol improving the impairment by reducing oxidative stress and tumor necrosis factor-α signaling. The anti-inflammatory effects of propranolol were further demonstrated in isoproterenol-stimulated BV2 and RAW264.7 cells through its ability to decrease cytokine production. Despite their potential benefits, stroke-associated hyperglycemia and inflammation are commonly linked with harmful consequences. Our findings provide new insight into the anti-inflammatory, neuroprotective, and hypoglycemic mechanisms of propranolol in combating neurodegenerative diseases, such as stroke. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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Review

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17 pages, 1669 KiB  
Review
Heat Shock Protein 70 (HSP70) Induction: Chaperonotherapy for Neuroprotection after Brain Injury
by Jong Youl Kim, Sumit Barua, Mei Ying Huang, Joohyun Park, Midori A. Yenari and Jong Eun Lee
Cells 2020, 9(9), 2020; https://doi.org/10.3390/cells9092020 - 2 Sep 2020
Cited by 44 | Viewed by 10516
Abstract
The 70 kDa heat shock protein (HSP70) is a stress-inducible protein that has been shown to protect the brain from various nervous system injuries. It allows cells to withstand potentially lethal insults through its chaperone functions. Its chaperone properties can assist in protein [...] Read more.
The 70 kDa heat shock protein (HSP70) is a stress-inducible protein that has been shown to protect the brain from various nervous system injuries. It allows cells to withstand potentially lethal insults through its chaperone functions. Its chaperone properties can assist in protein folding and prevent protein aggregation following several of these insults. Although its neuroprotective properties have been largely attributed to its chaperone functions, HSP70 may interact directly with proteins involved in cell death and inflammatory pathways following injury. Through the use of mutant animal models, gene transfer, or heat stress, a number of studies have now reported positive outcomes of HSP70 induction. However, these approaches are not practical for clinical translation. Thus, pharmaceutical compounds that can induce HSP70, mostly by inhibiting HSP90, have been investigated as potential therapies to mitigate neurological disease and lead to neuroprotection. This review summarizes the neuroprotective mechanisms of HSP70 and discusses potential ways in which this endogenous therapeutic molecule could be practically induced by pharmacological means to ultimately improve neurological outcomes in acute neurological disease. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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20 pages, 1260 KiB  
Review
Role of HMGB1 in the Interplay between NETosis and Thrombosis in Ischemic Stroke: A Review
by Seung-Woo Kim and Ja-Kyeong Lee
Cells 2020, 9(8), 1794; https://doi.org/10.3390/cells9081794 - 28 Jul 2020
Cited by 63 | Viewed by 7372
Abstract
Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to [...] Read more.
Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to the fact that the NETs serve as a scaffold for cells and numerous coagulation factors and stimulate fibrin deposition. A crosstalk between NETs and thrombosis has been indicated to play a role in numerous thrombosis-related conditions including stroke. In cerebral ischemia, neutrophils are the first group of cells to infiltrate the damaged brain tissue, where they produce NETs in the brain parenchyma and within blood vessels, thereby aggravating inflammation. Increasing evidences suggest the connection between NETosis and thrombosis as a possible cause of “tPA resistance”, a problem encountered during the treatment of stroke patients. Several damage-associated molecular pattern molecules have been proven to induce NETosis and thrombosis, with high mobility group box 1 (HMGB1) playing a critical role. This review discusses NETosis and thrombosis and their crosstalk in various thrombosis-related diseases, focusing on the role of HMGB1 as a mediator in stroke. We also addresses the function of peptidylarginine deiminase 4 with respect to the interplay with HMGB1 in NET-induced thrombosis. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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24 pages, 3153 KiB  
Review
Metabolome Changes in Cerebral Ischemia
by Tae Hwan Shin, Da Yeon Lee, Shaherin Basith, Balachandran Manavalan, Man Jeong Paik, Igor Rybinnik, M. Maral Mouradian, Jung Hwan Ahn and Gwang Lee
Cells 2020, 9(7), 1630; https://doi.org/10.3390/cells9071630 - 7 Jul 2020
Cited by 81 | Viewed by 7023
Abstract
Cerebral ischemia is caused by perturbations in blood flow to the brain that trigger sequential and complex metabolic and cellular pathologies. This leads to brain tissue damage, including neuronal cell death and cerebral infarction, manifesting clinically as ischemic stroke, which is the cause [...] Read more.
Cerebral ischemia is caused by perturbations in blood flow to the brain that trigger sequential and complex metabolic and cellular pathologies. This leads to brain tissue damage, including neuronal cell death and cerebral infarction, manifesting clinically as ischemic stroke, which is the cause of considerable morbidity and mortality worldwide. To analyze the underlying biological mechanisms and identify potential biomarkers of ischemic stroke, various in vitro and in vivo experimental models have been established investigating different molecular aspects, such as genes, microRNAs, and proteins. Yet, the metabolic and cellular pathologies of ischemic brain injury remain not fully elucidated, and the relationships among various pathological mechanisms are difficult to establish due to the heterogeneity and complexity of the disease. Metabolome-based techniques can provide clues about the cellular pathologic status of a condition as metabolic disturbances can represent an endpoint in biological phenomena. A number of investigations have analyzed metabolic changes in samples from cerebral ischemia patients and from various in vivo and in vitro models. We previously analyzed levels of amino acids and organic acids, as well as polyamine distribution in an in vivo rat model, and identified relationships between metabolic changes and cellular functions through bioinformatics tools. This review focuses on the metabolic and cellular changes in cerebral ischemia that offer a deeper understanding of the pathology underlying ischemic strokes and contribute to the development of new diagnostic and therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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28 pages, 1004 KiB  
Review
Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke
by Berta Puig, Denise Yang, Santra Brenna, Hermann Clemens Altmeppen and Tim Magnus
Cells 2020, 9(7), 1609; https://doi.org/10.3390/cells9071609 - 2 Jul 2020
Cited by 6 | Viewed by 3742
Abstract
Ischemic stroke belongs to the leading causes of mortality and disability worldwide. Although treatments for the acute phase of stroke are available, not all patients are eligible. There is a need to search for therapeutic options to promote neurological recovery after stroke. The [...] Read more.
Ischemic stroke belongs to the leading causes of mortality and disability worldwide. Although treatments for the acute phase of stroke are available, not all patients are eligible. There is a need to search for therapeutic options to promote neurological recovery after stroke. The cellular prion protein (PrPC) has been consistently linked to a neuroprotective role after ischemic damage: it is upregulated in the penumbra area following stroke in humans, and animal models of stroke have shown that lack of PrPC aggravates the ischemic damage and lessens the functional outcome. Mechanistically, these effects can be linked to numerous functions attributed to PrPC: (1) as a signaling partner of the PI3K/Akt and MAPK pathways, (2) as a regulator of glutamate receptors, and (3) promoting stem cell homing mechanisms, leading to angio- and neurogenesis. PrPC can be cleaved at different sites and the proteolytic fragments can account for the manifold functions. Moreover, PrPC is present on extracellular vesicles (EVs), released membrane particles originating from all types of cells that have drawn attention as potential therapeutic tools in stroke and many other diseases. Thus, identification of the many mechanisms underlying PrPC-induced neuroprotection will not only provide further understanding of the physiological functions of PrPC but also new ideas for possible treatment options after ischemic stroke. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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42 pages, 2294 KiB  
Review
Biomaterials to Neuroprotect the Stroke Brain: A Large Opportunity for Narrow Time Windows
by Daniel González-Nieto, Rocío Fernández-Serra, José Pérez-Rigueiro, Fivos Panetsos, Ricardo Martinez-Murillo and Gustavo V. Guinea
Cells 2020, 9(5), 1074; https://doi.org/10.3390/cells9051074 - 26 Apr 2020
Cited by 33 | Viewed by 6633
Abstract
Ischemic stroke represents one of the most prevalent pathologies in humans and is a leading cause of death and disability. Anti-thrombolytic therapy with tissue plasminogen activator (t-PA) and surgical thrombectomy are the primary treatments to recanalize occluded vessels and normalize the blood flow [...] Read more.
Ischemic stroke represents one of the most prevalent pathologies in humans and is a leading cause of death and disability. Anti-thrombolytic therapy with tissue plasminogen activator (t-PA) and surgical thrombectomy are the primary treatments to recanalize occluded vessels and normalize the blood flow in ischemic and peri-ischemic regions. A large majority of stroke patients are refractory to treatment or are not eligible due to the narrow time window of therapeutic efficacy. In recent decades, we have significantly increased our knowledge of the molecular and cellular mechanisms that inexorably lead to progressive damage in infarcted and peri-lesional brain areas. As a result, promising neuroprotective targets have been identified and exploited in several stroke models. However, these considerable advances have been unsuccessful in clinical contexts. This lack of clinical translatability and the emerging use of biomaterials in different biomedical disciplines have contributed to developing a new class of biomaterial-based systems for the better control of drug delivery in cerebral disorders. These systems are based on specific polymer formulations structured in nanoparticles and hydrogels that can be administered through different routes and, in general, bring the concentrations of drugs to therapeutic levels for prolonged times. In this review, we first provide the general context of the molecular and cellular mechanisms impaired by cerebral ischemia, highlighting the role of excitotoxicity, inflammation, oxidative stress, and depolarization waves as the main pathways and targets to promote neuroprotection avoiding neuronal dysfunction. In the second part, we discuss the versatile role played by distinct biomaterials and formats to support the sustained administration of particular compounds to neuroprotect the cerebral tissue at risk of damage. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cerebral Ischemia)
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