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Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms
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Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms

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 (20 April 2025) | Viewed by 13643

Special Issue Editor

Dr. Cesare Patrone

E-Mail Website
Guest Editor
NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden
Interests: stroke; diabetes; obesity; neuroplasticity; neurogenesis; neuroprotection

Special Issue Information

Dear Colleagues, 

Stroke is a leading cause of permanent disability. Although the handling of acute stroke has improved considerably in the past few decades, recent data revealed that two in three patients with ischemic stroke were either dead or functionally dependent at 5 years post-stroke. This underlines the importance of this clinical problem and the urgency to ameliorate post-stroke functional recovery. Additionally, the role of various stroke comorbidities is not fully understood. Although many studies describe the effect of comorbidities on stroke risk, relatively few have addressed their influence on post-stroke neurological recovery. 

In this Special Issue of the International Journal of Molecular Sciences, authors are invited to submit a wide range of papers related to neurological recovery after stroke. These papers can focus on potential therapeutic strategies and treatment techniques for stroke recovery, as well as describing the effects of stroke comorbidities such as diabetes, hypertension, obesity, and vascular complications. Papers addressing the identification of relevant mechanisms through which stroke recovery could be enhanced are also welcome, as are clinical studies.

Dr. Cesare Patrone
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
  • neurological recovery
  • complications
  • comorbidities
  • neuroplasticity
  • neuroinflammation
  • astrocytes
  • oligodendrocytes
  • microglia
  • stem cells

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Published Papers (5 papers)

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Research

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25 pages, 10236 KiB  
Article
Human-Brain-Derived Ischemia-Induced Stem Cell Transplantation Is Associated with a Greater Neurological Functional Improvement Compared with Human-Bone Marrow-Derived Mesenchymal Stem Cell Transplantation in Mice After Stroke
by Shuichi Tanada, Takayuki Nakagomi, Akiko Nakano-Doi, Toshinori Sawano, Shuji Kubo, Yoji Kuramoto, Kazutaka Uchida, Kenichi Yamahara, Nobutaka Doe and Shinichi Yoshimura
Int. J. Mol. Sci. 2024, 25(22), 12065; https://doi.org/10.3390/ijms252212065 - 10 Nov 2024
Viewed by 1330
Abstract
The transplantation of injury/ischemia-induced stem cells (iSCs) extracted from post-stroke human brains can improve the neurological functions of mice after stroke. However, the usefulness of iSCs as an alternative stem cell source remains unclear. The current study aimed to assess the efficacy of [...] Read more.
The transplantation of injury/ischemia-induced stem cells (iSCs) extracted from post-stroke human brains can improve the neurological functions of mice after stroke. However, the usefulness of iSCs as an alternative stem cell source remains unclear. The current study aimed to assess the efficacy of iSC and mesenchymal stem cell (MSC) transplantation. In this experiment, equal numbers of human brain-derived iSCs (h-iSCs) (5.0 × 104 cells/μL) and human bone marrow-derived MSCs (h-MSCs) (5.0 × 104 cells/μL) were intracranially transplanted into post-stroke mouse brains after middle cerebral artery occlusion. Results showed that not only h-iSC transplantation but also h-MSC transplantation activated endogenous neural stem/progenitor cells (NSPCs) around the grafted sites and promoted neurological functional improvement. However, mice that received h-iSC transplantation experienced improvement in a higher number of behavioral tasks compared with those that received h-MSC transplantation. To investigate the underlying mechanism, NSPCs extracted from the ischemic areas of post-stroke mouse brains were cocultured with h-iSCs or h-MSCs. After coincubation, NSPCs, h-iSCs, and h-MSCs were selectively collected via fluorescence-activated cell sorting. Next, their traits were analyzed via microarray analysis. The genes related to various neuronal lineages in NSPCs after coincubation with h-iSCs were enriched compared with those in NSPCs after coincubation with h-MSCs. In addition, the gene expression patterns of h-iSCs relative to those of h-MSCs showed that the expression of genes related to synapse formation and neurotransmitter-producing neurons increased more after coincubation with NSPCs. Hence, cell–cell interactions with NSPCs promoted transdifferentiation toward functional neurons predominantly in h-iSCs. In accordance with these findings, immunohistochemistry showed that the number of neuronal networks between NSPCs and h-iSCs was higher than that between NSPCs and h-MSCs. Therefore, compared with h-MSC transplantation, h-iSC transplantation is associated with a higher neurological functional improvement, presumably by more effectively modulating the fates of endogenous NSPCs and grafted h-iSCs themselves. Full article
(This article belongs to the Special Issue Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms)
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19 pages, 4364 KiB  
Article
TGF-β1 Decreases Microglia-Mediated Neuroinflammation and Lipid Droplet Accumulation in an In Vitro Stroke Model
by Wenqiang Xin, Yongli Pan, Wei Wei, Stefan T. Gerner, Sabine Huber, Martin Juenemann, Marius Butz, Mathias Bähr, Hagen B. Huttner and Thorsten R. Doeppner
Int. J. Mol. Sci. 2023, 24(24), 17329; https://doi.org/10.3390/ijms242417329 - 10 Dec 2023
Cited by 11 | Viewed by 2956
Abstract
Hypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-β1 in inflammation and LD accumulation in cultured microglia exposed to [...] Read more.
Hypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-β1 in inflammation and LD accumulation in cultured microglia exposed to hypoxia were analyzed herein. Primary microglia were exposed to oxygen-glucose deprivation (OGD) injury and lipopolysaccharide (LPS) stimulation. For analyzing the role of TGF-β1 patterns under such conditions, a TGF-β1 siRNA and an exogenous recombinant TGF-β1 protein were employed. Further studies applied Triacsin C, an inhibitor of LD formation, in order to directly assess the impact of LD formation on the modulation of inflammation. To assess mutual microglia-to-neuron interactions, a co-culture model of these cells was established. Upon OGD exposure, microglial TGF-β1 levels were significantly increased, whereas LPS stimulation yielded decreased levels. Elevating TGF-β1 expression proved highly effective in suppressing inflammation and reducing LD accumulation in microglia exposed to LPS. Conversely, inhibition of TGF-β1 led to the promotion of microglial cell inflammation and an increase in LD accumulation in microglia exposed to OGD. Employing the LD formation inhibitor Triacsin C, in turn, polarized microglia towards an anti-inflammatory phenotype. Such modulation of both microglial TGF-β1 and LD levels significantly affected the resistance of co-cultured neurons. This study provides novel insights by demonstrating that TGF-β1 plays a protective role against microglia-mediated neuroinflammation through the suppression of LD accumulation. These findings offer a fresh perspective on stroke treatment, suggesting the potential of targeting this pathway for therapeutic interventions. Full article
(This article belongs to the Special Issue Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms)
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18 pages, 2953 KiB  
Article
Multiplexing Biosensor for the Detection of Extracellular Vesicles as Biomarkers of Tissue Damage and Recovery after Ischemic Stroke
by Silvia Picciolini, Valentina Mangolini, Francesca Rodà, Angelo Montesano, Francesca Arnaboldi, Piergiuseppe Liuzzi, Andrea Mannini, Marzia Bedoni and Alice Gualerzi
Int. J. Mol. Sci. 2023, 24(9), 7937; https://doi.org/10.3390/ijms24097937 - 27 Apr 2023
Cited by 5 | Viewed by 2346
Abstract
The inflammatory, reparative and regenerative mechanisms activated in ischemic stroke patients immediately after the event cooperate in the response to injury, in the restoration of functions and in brain remodeling even weeks after the event and can be sustained by the rehabilitation treatment. [...] Read more.
The inflammatory, reparative and regenerative mechanisms activated in ischemic stroke patients immediately after the event cooperate in the response to injury, in the restoration of functions and in brain remodeling even weeks after the event and can be sustained by the rehabilitation treatment. Nonetheless, patients’ response to treatments is difficult to predict because of the lack of specific measurable markers of recovery, which could be complementary to clinical scales in the evaluation of patients. Considering that Extracellular Vesicles (EVs) are carriers of multiple molecules involved in the response to stroke injury, in the present study, we have identified a panel of EV-associated molecules that (i) confirm the crucial involvement of EVs in the processes that follow ischemic stroke, (ii) could possibly profile ischemic stroke patients at the beginning of the rehabilitation program, (iii) could be used in predicting patients’ response to treatment. By means of a multiplexing Surface Plasmon Resonance imaging biosensor, subacute ischemic stroke patients were proven to have increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) and translocator protein (TSPO) on the surface of small EVs in blood. Besides, microglia EVs and endothelial EVs were shown to be significantly involved in the intercellular communications that occur more than 10 days after ischemic stroke, thus being potential tools for the profiling of patients in the subacute phase after ischemic stroke and in the prediction of their recovery. Full article
(This article belongs to the Special Issue Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms)
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21 pages, 3239 KiB  
Article
The Pre-Stroke Induction and Normalization of Insulin Resistance Respectively Worsens and Improves Functional Recovery
by Ellen Vercalsteren, Dimitra Karampatsi, Doortje Dekens, Aikaterini Letsiou, Alexander Zabala, Mihaela Romanitan, Thomas Klein, Thomas Nyström, Vladimer Darsalia and Cesare Patrone
Int. J. Mol. Sci. 2023, 24(4), 3989; https://doi.org/10.3390/ijms24043989 - 16 Feb 2023
Cited by 1 | Viewed by 2602
Abstract
Type 2 diabetes (T2D) impairs post-stroke recovery, and the underlying mechanisms are unknown. Insulin resistance (IR), a T2D hallmark that is also closely linked to aging, has been associated with impaired post-stroke recovery. However, whether IR worsens stroke recovery is unknown. We addressed [...] Read more.
Type 2 diabetes (T2D) impairs post-stroke recovery, and the underlying mechanisms are unknown. Insulin resistance (IR), a T2D hallmark that is also closely linked to aging, has been associated with impaired post-stroke recovery. However, whether IR worsens stroke recovery is unknown. We addressed this question in mouse models where early IR, with or without hyperglycemia, was induced by chronic high-fat diet feeding or sucrose supplementation in the drinking water, respectively. Furthermore, we used 10-month-old mice, spontaneously developing IR but not hyperglycemia, where IR was normalized pharmacologically pre-stroke with Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and the density of striatal cholinergic interneurons were also assessed by immunohistochemistry/quantitative microscopy. Pre-stroke induction and normalization of IR, respectively, worsened and improved post-stroke neurological recovery. Moreover, our data indicate a potential association of this impaired recovery with exacerbated neuroinflammation and a decreased density of striatal cholinergic interneurons. The global diabetes epidemic and population aging are dramatically increasing the percentage of people in need of post-stroke treatment/care. Our results suggest that future clinical studies should target pre-stroke IR to reduce stroke sequelae in both diabetics and elderly people with prediabetes. Full article
(This article belongs to the Special Issue Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms)
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Review

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17 pages, 622 KiB  
Review
What Else Can Be Done by the Spinal Cord? A Review on the Effectiveness of Transpinal Direct Current Stimulation (tsDCS) in Stroke Recovery
by Paola Marangolo, Simona Vasta, Alessio Manfredini and Carlo Caltagirone
Int. J. Mol. Sci. 2023, 24(12), 10173; https://doi.org/10.3390/ijms241210173 - 15 Jun 2023
Cited by 2 | Viewed by 2134
Abstract
Since the spinal cord has traditionally been considered a bundle of long fibers connecting the brain to all parts of the body, the study of its role has long been limited to peripheral sensory and motor control. However, in recent years, new studies [...] Read more.
Since the spinal cord has traditionally been considered a bundle of long fibers connecting the brain to all parts of the body, the study of its role has long been limited to peripheral sensory and motor control. However, in recent years, new studies have challenged this view pointing to the spinal cord’s involvement not only in the acquisition and maintenance of new motor skills but also in the modulation of motor and cognitive functions dependent on cortical motor regions. Indeed, several reports to date, which have combined neurophysiological techniques with transpinal direct current stimulation (tsDCS), have shown that tsDCS is effective in promoting local and cortical neuroplasticity changes in animals and humans through the activation of ascending corticospinal pathways that modulate the sensorimotor cortical networks. The aim of this paper is first to report the most prominent tsDCS studies on neuroplasticity and its influence at the cortical level. Then, a comprehensive review of tsDCS literature on motor improvement in animals and healthy subjects and on motor and cognitive recovery in post-stroke populations is presented. We believe that these findings might have an important impact in the future making tsDCS a potential suitable adjunctive approach for post-stroke recovery. Full article
(This article belongs to the Special Issue Enhancing Neurological Recovery after Stroke: Potential Therapies and Mechanisms)
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