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Development of New Drugs against Stroke
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Development of New Drugs against Stroke

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 October 2022) | Viewed by 13556

Special Issue Editor

Dr. Antonio Henrique B. Martins

E-Mail Website
Guest Editor
Pharmacology and Toxicology Department, University of Puerto Rico, Medical Sciences Campus, Guillermo Arbona, Área de Centro Médico Río Piedras, PR 00935, USA
Interests: neuroprotection; blood–brain barrier; organophosphates; neuronal cell differentiation; kallikrein–kinin system

Special Issue Information

Dear Colleagues, 

Stroke affects 15 million people annually worldwide. Many factors can increase the stroke risk, such as obesity, high cholesterol, and diabetes. It is a complex disease, and due to the high selectivity of the blood–brain barrier, the likelihood of generating new drugs that affect this brain illness is low. Just one FDA-approved drug has become the gold standard for treating ischemic stroke—tissue plasminogen activator (tPA). Nevertheless, an abysmally low number of patients are qualified to receive tPA due to its limited time window and contraindications. Although it is effective for those who qualify, it is not neuroprotective. Several drugs can induce neuroprotection in vitro or ex vivo but fail in crossing the blood–brain barrier. For this reason, it is imperative to develop new treatments that induce direct neuroprotection, decrease the blood–brain barrier permeation, and modulate inflammation. Most of the work studying the effects of neuroprotective or anti-inflammatory drugs is performed using healthy animal models. Thus, to increase the repertory of studies using neuroprotective or anti-inflammatory drugs in models (in vivo, in vitro, or ex vivo models) that mimic the people or conditions that lead to the risk of stroke, we have decided to launch a Special Issue with the following topics related to ischemia, including but not limited to stroke comorbidities such as diabetes, hypertension, and obesity, using drugs that: (1) decrease the blood–brain barrier disruption, (2) induce neuroprotection, (3) modulate the peripheral and/or central inflammation, (4) drive the differentiation of neural progenitor cells to neurons, (5) decrease reactive oxygen species after reperfusion or reoxygenation (in case of in vitro studies), (6) modulate microglial anti-inflammatory state and (7) make use of nanotechnology-based drug delivery to the brain.  This Special Issue focuses on the preclinical molecular research.  

Dr. Antonio Henrique B. Martins
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

  • ischemic stroke
  • neuroprotection
  • blood–brain barrier
  • stroke comorbidities
  • brain drug delivery
  • neural progenitor cells
  • nanotechnology
  • natural products

Published Papers (4 papers)

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Research

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20 pages, 3815 KiB  
Article
Network Pharmacology Analysis and Experimental Validation of Kaempferol in the Treatment of Ischemic Stroke by Inhibiting Apoptosis and Regulating Neuroinflammation Involving Neutrophils
by Shan-Shan Zhang, Man Liu, Dong-Ni Liu, Yu-Fu Shang, Guan-Hua Du and Yue-Hua Wang
Int. J. Mol. Sci. 2022, 23(20), 12694; https://doi.org/10.3390/ijms232012694 - 21 Oct 2022
Cited by 16 | Viewed by 2314
Abstract
Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in [...] Read more.
Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in the treatment of cerebral ischemia. First, network pharmacology analysis identified the biological process of kaempferol, suggesting that kaempferol may partly help in treating ischemic stroke by regulating apoptosis and inflammatory response. Then, we evaluated the efficacy of kaempferol in the acute stage of ischemic stroke and elucidated its effects and possible mechanisms on cell apoptosis and neuroinflammation involved by neutrophils. The results showed that kaempferol could significantly reduce the modified neurological severity score (mNSS), and reduce the volume of cerebral infarction and the degree of cerebral edema. In terms of anti-apoptosis, kaempferol could significantly reduce the number of TUNEL-positive cells, inhibit the expression of pro-apoptotic proteins and promote the expression of anti-apoptotic proteins. Kaempferol may play an anti-apoptotic role by up-regulating the expression level of the BDNF-TrkB-PI3K/AKT signaling pathway. In addition, we found that kaempferol inhibited neuron loss and the activation of glial cells, as well as the expression level of the inflammatory protein COX-2 and the classic pro-inflammatory signaling pathway TLR4/MyD88/NF-κB in the ischemic brain, reduced MPO activity and neutrophil counts in peripheral blood, and down-regulated neutrophil aggregation and infiltration in the ischemic brain. Western blot revealed that kaempferol down-regulated the activation of the JAK1/STAT3 signaling pathway in neutrophils and ischemic brains. Our study showed that kaempferol inhibited the activation and number of neutrophils in the rat peripheral blood and brain, which may be related to the down-regulation of the JAK1/STAT3 pathway. Full article
(This article belongs to the Special Issue Development of New Drugs against Stroke)
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19 pages, 2444 KiB  
Article
Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations
by Rocío Fernández-Serra, Emma Martínez-Alonso, Alberto Alcázar, Mourad Chioua, José Marco-Contelles, Ricardo Martínez-Murillo, Milagros Ramos, Gustavo V. Guinea and Daniel González-Nieto
Int. J. Mol. Sci. 2022, 23(13), 7449; https://doi.org/10.3390/ijms23137449 - 04 Jul 2022
Cited by 4 | Viewed by 2197
Abstract
Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative [...] Read more.
Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies. Full article
(This article belongs to the Special Issue Development of New Drugs against Stroke)
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Review

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25 pages, 1371 KiB  
Review
The Development of Novel Drug Treatments for Stroke Patients: A Review
by Dmitry Frank, Alexander Zlotnik, Matthew Boyko and Benjamin Fredrick Gruenbaum
Int. J. Mol. Sci. 2022, 23(10), 5796; https://doi.org/10.3390/ijms23105796 - 21 May 2022
Cited by 20 | Viewed by 5979
Abstract
Acute ischemic stroke is a critical condition that can result in disability and death. The consequences of this medical condition depend on various factors, including the size of the stroke, affected brain region, treatment onset, and the type of treatment. The primary objective [...] Read more.
Acute ischemic stroke is a critical condition that can result in disability and death. The consequences of this medical condition depend on various factors, including the size of the stroke, affected brain region, treatment onset, and the type of treatment. The primary objective of stroke treatment is to restart ischemic penumbra tissue perfusion and reduce infarct volume by sustaining blood flow. Recent research on the condition’s pathological pathways and processes has significantly improved treatment options beyond restoring perfusion. Many studies have concentrated on limiting injury severity via the manipulation of molecular mechanisms of ischemia, particularly in animal research. This article reviews completed and ongoing research on the development of acute ischemic stroke drugs. This study focuses on three main categories of antithrombotic drugs, thrombolytic drugs, and neuroprotective agents. The paper outlines findings from animal and clinical trials and explores the working mechanisms of these drugs. Full article
(This article belongs to the Special Issue Development of New Drugs against Stroke)
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Other

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8 pages, 264 KiB  
Perspective
From Kidney Protection to Stroke Prevention: The Potential Role of Sodium Glucose Cotransporter-2 Inhibitors
by Cheng-Yang Hsieh and Sheng-Feng Sung
Int. J. Mol. Sci. 2023, 24(1), 351; https://doi.org/10.3390/ijms24010351 - 26 Dec 2022
Cited by 5 | Viewed by 2416
Abstract
Chronic kidney disease (CKD) is an independent risk factor for stroke and covert cerebrovascular disease, and up to 40% of stroke patients have concomitant CKD. However, the so-called “cerebrorenal interaction” attracted less attention compared to its cardiorenal counterpart. Diabetes is the leading cause [...] Read more.
Chronic kidney disease (CKD) is an independent risk factor for stroke and covert cerebrovascular disease, and up to 40% of stroke patients have concomitant CKD. However, the so-called “cerebrorenal interaction” attracted less attention compared to its cardiorenal counterpart. Diabetes is the leading cause of CKD. The sodium–glucose cotransporter (SGLT) 2 inhibitor is a relatively new class of oral anti-diabetic drugs and has cardiorenal benefits in addition to glucose-lowering effects. In the present perspective, we would like to review the current status and future potential of the SGLT2 inhibitor in cerebro–renal interactions and strokes regardless of the status of diabetes. We propose the potential roles of baseline renal functions and SGLT1/2 dual inhibition in stroke prevention, as well as the additional benefits of reducing atrial fibrillation and hemorrhagic stroke for SGLT2 inhibitors. Further clinical trials are anticipated to test whether SGLT2 inhibitors can fulfill the long-standing unmet clinical need and stop such a vicious cycle of cerebro–renal interaction. Full article
(This article belongs to the Special Issue Development of New Drugs against Stroke)
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