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Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0
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Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0

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 September 2022) | Viewed by 26809

Special Issue Editor

Prof. Dr. Cesar Borlongan

E-Mail Website
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. A 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

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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.

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Keywords

  • Stroke
  • Neuroprotection
  • Neuroregeneration

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Published Papers (7 papers)

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Research

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18 pages, 831 KiB  
Article
Fatty Acids and Lipid Paradox-Neuroprotective Biomarkers in Ischemic Stroke
by Sebastian Andone, Lénárd Farczádi, Silvia Imre and Rodica Bălașa
Int. J. Mol. Sci. 2022, 23(18), 10810; https://doi.org/10.3390/ijms231810810 - 16 Sep 2022
Cited by 6 | Viewed by 2179
Abstract
Stroke is the primary cause of death and disability worldwide, with ischemic stroke up to 80% of the total cases. Lipid profile was established as a major risk factor for stroke, but recent studies show a paradoxical relationship between serum values and the [...] Read more.
Stroke is the primary cause of death and disability worldwide, with ischemic stroke up to 80% of the total cases. Lipid profile was established as a major risk factor for stroke, but recent studies show a paradoxical relationship between serum values and the outcome of stroke patients. Our study aims to analyze the impact of the classic extended lipid profile, including fatty acids as potential neuroprotective biomarkers for the outcome of ischemic stroke patients. We included 298 patients and collected clinical, paraclinical, and outcome parameters. We used a method consisting of high-performance liquid chromatography coupled with mass spectrometry to quantify serum fatty acids. We observed a negative correlation between National Institutes of Health Stroke Scale (NIHSS) at admission and total cholesterol (p = 0.040; r = −0.120), respectively triglycerides (p = 0.041; r = −0.122). The eicosapentaenoic to arachidonic acid ratio has a negative correlation, while the docosahexaenoic to eicosapentaenoic acid ratio positively correlates with all the prognostic parameters, showing a potential neuroprotective role for eicosapentaenoic acid in preventing severe ischemic stroke. The impact of the lipid profile paradox and the dependency relationship with the fatty acids represent a significant predictive factor for the functional and disability prognostic of ischemic stroke patients. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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15 pages, 1226 KiB  
Article
CCL5 Levels Predict Stroke Volume Growth in Acute Ischemic Stroke and Significantly Diminish in Hemorrhagic Stroke Patients
by Francisco José Julián-Villaverde, Marta Serrano-Ponz, Enrique Ramalle-Gómara, Alfredo Martínez and Laura Ochoa-Callejero
Int. J. Mol. Sci. 2022, 23(17), 9967; https://doi.org/10.3390/ijms23179967 - 1 Sep 2022
Cited by 5 | Viewed by 2448
Abstract
Stroke remains an important health challenge. Here, we study whether circulating chemokine (C-C motif) ligand 5 (CCL5) levels may predict clinical outcomes for stroke patients. A total of 100 consecutive stroke patients (36 acute ischemic and 64 hemorrhagic) were admitted to the stroke [...] Read more.
Stroke remains an important health challenge. Here, we study whether circulating chemokine (C-C motif) ligand 5 (CCL5) levels may predict clinical outcomes for stroke patients. A total of 100 consecutive stroke patients (36 acute ischemic and 64 hemorrhagic) were admitted to the stroke unit. Clinical history data and monitoring parameters were recorded. Blood serum was collected at days 0, 1, and hospital discharge to measure CCL5 levels by ELISA. Infarct or hemorrhagic volume, neurological severity (NIHSS), and functional prognosis (mRankin scale) were measured as clinical outcomes. CCL5 levels were lower in patients with hemorrhagic stroke than in patients with acute ischemic stroke. No differences were found between females and males in both types of stroke. Ischemic stroke patients whose infarct volume grew had lower CCL5 levels at day 0. Levels of CCL5 in ischemic and hemorrhagic patients were not associated with more severe symptoms/worse prognosis (NIHSS > 3; mRankin > 2) at admission or at 3 months. CCL5 could be used as a diagnostic marker to distinguish between ischemic and hemorrhagic strokes. Furthermore, CCL5 levels could predict the infarct volume outcomes in ischemic patients. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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Review

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35 pages, 1106 KiB  
Review
Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches
by Carlo Domenico Maida, Rosario Luca Norrito, Salvatore Rizzica, Marco Mazzola, Elisa Rita Scarantino and Antonino Tuttolomondo
Int. J. Mol. Sci. 2024, 25(12), 6297; https://doi.org/10.3390/ijms25126297 - 7 Jun 2024
Cited by 1 | Viewed by 3210
Abstract
Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial [...] Read more.
Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischemia. ncRNAs, particularly microRNAs, and long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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17 pages, 544 KiB  
Review
Neuroprotective Strategies for Ischemic Stroke—Future Perspectives
by Matteo Haupt, Stefan T. Gerner, Mathias Bähr and Thorsten R. Doeppner
Int. J. Mol. Sci. 2023, 24(5), 4334; https://doi.org/10.3390/ijms24054334 - 22 Feb 2023
Cited by 56 | Viewed by 8812
Abstract
Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral [...] Read more.
Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from “traditional” neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity, stem-cell-based treatment methods are also considered. Furthermore, an overview of a prospective neuroprotective method using extracellular vesicles that are secreted from various stem cell sources, including neural stem cells and bone marrow stem cells, is also given. The review concludes with a short discussion on the microbiota–gut–brain axis that may serve as a potential target for future neuroprotective therapies. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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13 pages, 3355 KiB  
Review
Rodent Models of Post-Stroke Dementia
by Hahn Young Kim, Dong Bin Back, Bo-Ryoung Choi, Dong-Hee Choi and Kyoung Ja Kwon
Int. J. Mol. Sci. 2022, 23(18), 10750; https://doi.org/10.3390/ijms231810750 - 15 Sep 2022
Cited by 3 | Viewed by 3369
Abstract
Post-stroke cognitive impairment is one of the most common complications in stroke survivors. Concomitant vascular risk factors, including aging, diabetes mellitus, hypertension, dyslipidemia, or underlying pathologic conditions, such as chronic cerebral hypoperfusion, white matter hyperintensities, or Alzheimer’s disease pathology, can predispose patients to [...] Read more.
Post-stroke cognitive impairment is one of the most common complications in stroke survivors. Concomitant vascular risk factors, including aging, diabetes mellitus, hypertension, dyslipidemia, or underlying pathologic conditions, such as chronic cerebral hypoperfusion, white matter hyperintensities, or Alzheimer’s disease pathology, can predispose patients to develop post-stroke dementia (PSD). Given the various clinical conditions associated with PSD, a single animal model for PSD is not possible. Animal models of PSD that consider these diverse clinical situations have not been well-studied. In this literature review, diverse rodent models that simulate the various clinical conditions of PSD have been evaluated. Heterogeneous rodent models of PSD are classified into the following categories: surgical technique, special structure, and comorbid condition. The characteristics of individual models and their clinical significance are discussed in detail. Diverse rodent models mimicking the specific pathomechanisms of PSD could provide effective animal platforms for future studies investigating the characteristics and pathophysiology of PSD. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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26 pages, 719 KiB  
Review
The Role of DNA Methylation in Stroke Recovery
by Dong-Hee Choi, In-Ae Choi and Jongmin Lee
Int. J. Mol. Sci. 2022, 23(18), 10373; https://doi.org/10.3390/ijms231810373 - 8 Sep 2022
Cited by 11 | Viewed by 3247
Abstract
Epigenetic alterations affect the onset of ischemic stroke, brain injury after stroke, and mechanisms of poststroke recovery. In particular, DNA methylation can be dynamically altered by maintaining normal brain function or inducing abnormal brain damage. DNA methylation is regulated by DNA methyltransferase (DNMT), [...] Read more.
Epigenetic alterations affect the onset of ischemic stroke, brain injury after stroke, and mechanisms of poststroke recovery. In particular, DNA methylation can be dynamically altered by maintaining normal brain function or inducing abnormal brain damage. DNA methylation is regulated by DNA methyltransferase (DNMT), which promotes methylation, DNA demethylase, which removes methyl groups, and methyl-cytosine–phosphate–guanine-binding domain (MBD) protein, which binds methylated DNA and inhibits gene expression. Investigating the effects of modulating DNMT, TET, and MBD protein expression on neuronal cell death and neurorepair in ischemic stroke and elucidating the underlying mechanisms can facilitate the formulation of therapeutic strategies for neuroprotection and promotion of neuronal recovery after stroke. In this review, we summarize the role of DNA methylation in neuroprotection and neuronal recovery after stroke according to the current knowledge regarding the effects of DNA methylation on excitotoxicity, oxidative stress, apoptosis, neuroinflammation, and recovery after ischemic stroke. This review of the literature regarding the role of DNA methylation in neuroprotection and functional recovery after stroke may contribute to the development and application of novel therapeutic strategies for stroke. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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14 pages, 1357 KiB  
Review
Neuroprotection in Stroke—Focus on the Renin-Angiotensin System: A Systematic Review
by Sebastian Andone, Zoltan Bajko, Anca Motataianu, Smaranda Maier, Laura Barcutean and Rodica Balasa
Int. J. Mol. Sci. 2022, 23(7), 3876; https://doi.org/10.3390/ijms23073876 - 31 Mar 2022
Cited by 9 | Viewed by 2626
Abstract
Stroke is the primary cause of disability in the adult population. Hypertension represents the leading risk factor being present in almost half the patients. The renin-angiotensin system is involved in the physiopathology of stroke and has an essential impact on hypertension as a [...] Read more.
Stroke is the primary cause of disability in the adult population. Hypertension represents the leading risk factor being present in almost half the patients. The renin-angiotensin system is involved in the physiopathology of stroke and has an essential impact on hypertension as a risk factor. This article targeted the role of the renin-angiotensin system in stroke neuroprotection by reviewing the current literature available. The mechanism of action of the renin-angiotensin system was observed through the effects on AT1, AT2, and Mas receptors. The neuroprotective properties ascertained by angiotensin in stroke seem to be independent of the blood pressure reduction mechanism, and include neuroregeneration, angiogenesis, and increased neuronal resistance to hypoxia. The future relationship of stroke and the renin-angiotensin system is full of possibilities, as new agonist molecules emerge as potential candidates to restrict the impairment caused by stroke. Full article
(This article belongs to the Special Issue Stroke: Merging Neuroprotection and Neuroregeneration towards Therapeutics 2.0)
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