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Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 25361

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Special Issue Editor

Prof. Dr. Cesar Borlongan

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Guest Editor

Department of Neurosurgery, MDC 78, University of South Florida College Medicine, Tampa, FL 33612, USA
Interests: stem cell therapy; stroke, neonatal hypoxic-ischemic injury; Parkinson's disease; traumatic brain injury; translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will assemble stroke researchers and clinicians who have a vested interest in improving therapeutic outcomes in ischemic stroke. Although treatment options for stroke remain limited, tissue plasminogen activator or tPA and mechanical thrombectomy have seen their therapeutic windows extended to 4.5 hours and 24 hours after stroke onset, respectively. These wider times to initiate treatment intervention allow a larger population of stroke patients to benefit from these therapies. However, there remain more than 90% of stroke patients who will still be ineligible for treatment with tPA and thrombectomy. Combination of novel neuroprotective and neuroregenerative therapies, such as remote limb conditioning and localized hypothermia under the setting of tPA and thrombectomy, may further increase the therapeutic window and enhance functional outcomes in stroke. The merger of acute neuroprotection and delayed neuroregeneration represents an emerging field in stroke therapeutics. Understanding the molecular mechanisms of these therapies is the main focus of this issue.

Prof. Dr. Cesar Borlongan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Stroke
Neuroprotection
Neuroregeneration
neonatal hypoxic-ischemic injury
Parkinson’s disease
traumatic brain injury

Published Papers (7 papers)

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Research

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13 pages, 3772 KiB

Open AccessArticle

Human Milk Oligosaccharide 2′-Fucosyllactose Induces Neuroprotection from Intracerebral Hemorrhage Stroke

by Tsai-Wei Hung, Kuo-Jen Wu, Yu-Syuan Wang, Eun-Kyung Bae, YoungHa Song, JongWon Yoon and Seong-Jin Yu

Int. J. Mol. Sci. 2021, 22(18), 9881; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189881 - 13 Sep 2021

Cited by 5 | Viewed by 2856

Abstract

Intracerebral hemorrhage (ICH) occurs when brain blood vessels rupture, causing inflammation and cell death. 2-Fucosyllactose (2FL), a human milk oligosaccharide, has potent antiapoptotic and anti-inflammatory effects. The purpose of this study was to examine the protective effect of 2FL in cellular and rodent models of ICH. Hemin was added to a primary rat cortical neuronal and BV2 microglia coculture to simulate ICH in vitro. IBA1 and MAP2 immunoreactivities were used to determine inflammation and neuronal survival. Hemin significantly increased IBA1, while it reduced MAP2 immunoreactivity. 2FL significantly antagonized both responses. The protective effect of 2FL was next examined in a rat ICH model. Intracerebral administration of type VII collagenase reduced open-field locomotor activity. Early post-treatment with 2FL significantly improved locomotor activity. Brain tissues were collected for immunohistochemistry and qRT-PCR analysis. 2FL reduced IBA1 and CD4 immunoreactivity in the lesioned striatum. 2FL downregulated the expression of ER stress markers (PERK and CHOP), while it upregulated M2 macrophage markers (CD206 and TGFβ) in the lesioned brain. Taken together, our data support that 2FL has a neuroprotective effect against ICH through the inhibition of neuroinflammation and ER stress. 2FL may have clinical implications for the treatment of ICH. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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22 pages, 4027 KiB

Open AccessArticle

PTD4 Peptide Increases Neural Viability in an In Vitro Model of Acute Ischemic Stroke

by Jarosław Mazuryk, Izabela Puchalska, Kamil Koziński, Magdalena J. Ślusarz, Jarosław Ruczyński, Piotr Rekowski, Piotr Rogujski, Rafał Płatek, Marta Barbara Wiśniewska, Arkadiusz Piotrowski, Łukasz Janus, Piotr M. Skowron, Michał Pikuła, Paweł Sachadyn, Sylwia Rodziewicz-Motowidło, Artur Czupryn and Piotr Mucha

Int. J. Mol. Sci. 2021, 22(11), 6086; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116086 - 04 Jun 2021

Cited by 4 | Viewed by 4351

Abstract

Ischemic stroke is a disturbance in cerebral blood flow caused by brain tissue ischemia and hypoxia. We optimized a multifactorial in vitro model of acute ischemic stroke using rat primary neural cultures. This model was exploited to investigate the pro-viable activity of cell-penetrating peptides: arginine-rich Tat(49–57)-NH₂ (R⁴⁹KKRRQRRR⁵⁷-amide) and its less basic analogue, PTD4 (Y⁴⁷ARAAARQARA⁵⁷-amide). Our model included glucose deprivation, oxidative stress, lactic acidosis, and excitotoxicity. Neurotoxicity of these peptides was excluded below a concentration of 50 μm, and PTD4-induced pro-survival was more pronounced. Circular dichroism spectroscopy and molecular dynamics (MD) calculations proved potential contribution of the peptide conformational properties to neuroprotection: in MD, Tat(49–57)-NH₂ adopted a random coil and polyproline type II helical structure, whereas PTD4 adopted a helical structure. In an aqueous environment, the peptides mostly adopted a random coil conformation (PTD4) or a polyproline type II helical (Tat(49–57)-NH₂) structure. In 30% TFE, PTD4 showed a tendency to adopt a helical structure. Overall, the pro-viable activity of PTD4 was not correlated with the arginine content but rather with the peptide’s ability to adopt a helical structure in the membrane-mimicking environment, which enhances its cell membrane permeability. PTD4 may act as a leader sequence in novel drugs for the treatment of acute ischemic stroke. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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13 pages, 3020 KiB

Open AccessArticle

AKAP12 Supports Blood-Brain Barrier Integrity against Ischemic Stroke

by Ji Hae Seo, Takakuni Maki, Nobukazu Miyamoto, Yoon Kyong Choi, Kelly K. Chung, Gen Hamanaka, Ji Hyun Park, Emiri T. Mandeville, Hajime Takase, Kazuhide Hayakawa, Josephine Lok, Irwin H. Gelman, Kyu-Won Kim, Eng H. Lo and Ken Arai

Int. J. Mol. Sci. 2020, 21(23), 9078; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239078 - 28 Nov 2020

Cited by 11 | Viewed by 2940

Abstract

A-kinase anchor protein 12 (AKAP12) is a scaffolding protein that associates with intracellular molecules to regulate multiple signal transductions. Although the roles of AKAP12 in the central nervous system are still relatively understudied, it was previously shown that AKAP12 regulates blood-retinal barrier formation. In this study, we asked whether AKAP12 also supports the function and integrity of the blood-brain barrier (BBB). In a mouse model of focal ischemia, the expression level of AKAP12 in cerebral endothelial cells was upregulated during the acute phase of stroke. Also, in cultured cerebral endothelial cells, oxygen-glucose deprivation induced the upregulation of AKAP12. When AKAP12 expression was suppressed by an siRNA approach in cultured endothelial cells, endothelial permeability was increased along with the dysregulation of ZO-1/Claudin 5 expression. In addition, the loss of AKAP12 expression caused an upregulation/activation of the Rho kinase pathway, and treatment of Rho kinase inhibitor Y-27632 mitigated the increase of endothelial permeability in AKAP12-deficient endothelial cell cultures. These in vitro findings were confirmed by our in vivo experiments using Akap12 knockout mice. Compared to wild-type mice, Akap12 knockout mice showed a larger extent of BBB damage after stroke. However, the inhibition of rho kinase by Y-27632 tightened the BBB in Akap12 knockout mice. These data may suggest that endogenous AKAP12 works to alleviate the damage and dysfunction of the BBB caused by ischemic stress. Therefore, the AKAP12-rho-kinase signaling pathway represents a novel therapeutic target for stroke. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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14 pages, 2754 KiB

Open AccessArticle

Protective Effect of CXCR4 Antagonist CX807 in a Rat Model of Hemorrhagic Stroke

by Seong-Jin Yu, Kuo-Jen Wu, Yu-Syuan Wang, Jen-Shin Song, Chien-Huang Wu, Jiing-Jyh Jan, Eunkyung Bae, Hsi Chen, Kak-Shan Shia and Yun Wang

Int. J. Mol. Sci. 2020, 21(19), 7085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197085 - 25 Sep 2020

Cited by 16 | Viewed by 2498

Abstract

Intracerebral hemorrhage (ICH) is a major cause of stroke, with high mortality and morbidity. There is no effective pharmacological therapy for ICH. Previous studies have indicated that CXCR4 antagonists reduced microglia activation, attenuated infiltration of T cells, and improved functional recovery in ischemic stroke animals. The interaction of CXCR4 antagonists and ICH has not been characterized. The purpose of this study is to examine the neuroprotective action of a novel CXCR4 antagonist CX807 against ICH. In primary cortical neuronal and BV2 microglia co-culture, CX807 reduced glutamate-mediated neuronal loss and microglia activation. Adult rats were locally administered with collagenase VII to induce ICH. CX807 was given systemically after the ICH. Early post-treatment with CX807 improved locomotor activity in ICH rats. Brain tissues were collected for qRTPCR and histological staining. ICH upregulated the expression of CXCR4, CD8, TNFα, IL6, and TLR4. The immunoreactivity of IBA1 and CD8, as well as TUNEL labeling, were enhanced in the perilesioned area. CX807 significantly mitigated these responses. In conclusion, our data suggest that CX807 is neuroprotective and anti-inflammatory against ICH. CX807 may have clinical implications for the treatment of hemorrhagic stroke. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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15 pages, 2615 KiB

Open AccessArticle

Characterization of Tauopathy in a Rat Model of Post-Stroke Dementia Combining Acute Infarct and Chronic Cerebral Hypoperfusion

by Dong Bin Back, Bo-Ryoung Choi, Jung-Soo Han, Kyoung Ja Kwon, Dong-Hee Choi, Chan Young Shin, Jongmin Lee and Hahn Young Kim

Int. J. Mol. Sci. 2020, 21(18), 6929; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186929 - 21 Sep 2020

Cited by 17 | Viewed by 2720

Abstract

Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated the cognitive impairment and pathomechanism associated with tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH). We performed middle cerebral artery occlusion (MCAO) surgery in rats to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic function. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was combined with MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the peri-infarct area when CCH was combined. Synergistic accentuation of tauopathy was evident in the white matter. Microtubules in the neuronal axon and myelin sheath showed partial colocalization with the hyperphosphorylated tau, whereas oligodendrocytes showed near-complete colocalization. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest a hypothesis that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through the glymphatic system. Therapeutic strategies to improve the clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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Review

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28 pages, 763 KiB

Open AccessReview

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

by Milena Jankovic, Bojana Petrovic, Ivana Novakovic, Slavko Brankovic, Natasa Radosavljevic and Dejan Nikolic

Int. J. Mol. Sci. 2022, 23(3), 1601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031601 - 29 Jan 2022

Cited by 6 | Viewed by 3435

Abstract

Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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14 pages, 4757 KiB

Open AccessReview

Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke

by Shashank Shekhar, Yedan Liu, Shaoxun Wang, Huawei Zhang, Xing Fang, Jin Zhang, Letao Fan, Baoying Zheng, Richard J. Roman, Zhen Wang, Fan Fan and George W. Booz

Int. J. Mol. Sci. 2021, 22(4), 2074; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042074 - 19 Feb 2021

Cited by 34 | Viewed by 5472

Abstract

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca²⁺ influx through TRPC6 activates the cAMP (adenosine 3’,5’-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-d-aspartate (NMDA) receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells, such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood–brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management. Full article

(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics)

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