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New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection...
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New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 13337

Special Issue Editors

Prof. Dr. Matthias L. Riess

E-Mail Website
Guest Editor
1. Anesthesiology, TVHS VA Medical Center, 1310 24th Avenue South, Nashville, TN 37212, USA
2. Departments of Anesthesiology and Pharmacology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA
Interests: anesthesiology; pharmacology; physiology; cardiac arrest; vascular
Dr. Detlef Obal

E-Mail Website
Guest Editor
MD, PhD, DESA, University Medical Line, Department of Anesthesiology, Perioperative, and Pain Medicine Cardiovascular Institute, Stanford University, Stanford, CA, USA
Interests: iPSC-CM; iPSC-EC; hESC; personalized medicine; anesthesia; drug development; SDF-1

Special Issue Information

Dear Colleagues,

Cardiovascular disease is a significant health burden which is steadily rising. Ischemia/reperfusion injury to vital organs such as the heart and brain, encountered during myocardial infarction, stroke, and/or cardiac arrest, often results in death or permanent disability. Although ischemia already causes enormous detriment, the reintroduction of blood flow during reperfusion is thought to contribute even more to the overall injury. Thus, novel strategies to reduce vital organ injury during ischemia and upon reperfusion are desperately needed. 

This Special Issue of Cells is designed to highlight new developments in pharmacological drug discovery to specifically aid in neuro- and cardioprotection. We welcome high-quality basic science and translational studies that contribute to progress in this important field.

Prof. Dr. Matthias L. Riess
Dr. Detlef Obal
Guest Editors

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. 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.

Published Papers (7 papers)

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Research

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23 pages, 4445 KiB  
Article
Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
by Rishabh C. Choudhary, Muhammad Shoaib, Kei Hayashida, Tai Yin, Santiago J. Miyara, Cristina d’Abramo, William G. Heuser, Koichiro Shinozaki, Nancy Kim, Ryosuke Takegawa, Mitsuaki Nishikimi, Timmy Li, Casey Owens, Ernesto P. Molmenti, Mingzhu He, Sonya Vanpatten, Yousef Al-Abed, Junhwan Kim and Lance B. Becker
Cells 2023, 12(11), 1548; https://doi.org/10.3390/cells12111548 - 05 Jun 2023
Viewed by 2163
Abstract
Background: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated [...] Read more.
Background: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated metabolic pathways elicited following cardiac arrest have failed to demonstrate clear benefit. Many scientists have opined on the need for novel, multidimensional approaches to the multiple metabolic disturbances after cardiac arrest. In the current study, we have developed a therapeutic cocktail that includes ten drugs capable of targeting multiple pathways of ischemia–reperfusion injury after CA. We then evaluated its effectiveness in improving neurologically favorable survival through a randomized, blind, and placebo-controlled study in rats subjected to 12 min of asphyxial CA, a severe injury model. Results: 14 rats were given the cocktail and 14 received the vehicle after resuscitation. At 72 h post-resuscitation, the survival rate was 78.6% among cocktail-treated rats, which was significantly higher than the 28.6% survival rate among vehicle-treated rats (log-rank test; p = 0.006). Moreover, in cocktail-treated rats, neurological deficit scores were also improved. These survival and neurological function data suggest that our multi-drug cocktail may be a potential post-CA therapy that deserves clinical translation. Conclusions: Our findings demonstrate that, with its ability to target multiple damaging pathways, a multi-drug therapeutic cocktail offers promise both as a conceptual advance and as a specific multi-drug formulation capable of combatting neuronal degeneration and death following cardiac arrest. Clinical implementation of this therapy may improve neurologically favorable survival rates and neurological deficits in patients suffering from cardiac arrest. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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14 pages, 2690 KiB  
Article
Newly Developed Di-Block Copolymer-Based Cell Membrane Stabilizers Protect Mouse Coronary Artery Endothelial Cells against Hypoxia/Reoxygenation Injury
by Zhu Li, Mukesh K. Gupta, Matthew B. Barajas, Takuro Oyama, Craig L. Duvall and Matthias L. Riess
Cells 2023, 12(10), 1394; https://doi.org/10.3390/cells12101394 - 15 May 2023
Cited by 1 | Viewed by 1163
Abstract
Reperfusion after ischemia causes additional cellular damage, known as reperfusion injury, for which there is still no effective remedy. Poloxamer (P)188, a tri-block copolymer-based cell membrane stabilizer (CCMS), has been shown to provide protection against hypoxia/reoxygenation (HR) injury in various models by reducing [...] Read more.
Reperfusion after ischemia causes additional cellular damage, known as reperfusion injury, for which there is still no effective remedy. Poloxamer (P)188, a tri-block copolymer-based cell membrane stabilizer (CCMS), has been shown to provide protection against hypoxia/reoxygenation (HR) injury in various models by reducing membrane leakage and apoptosis and improving mitochondrial function. Interestingly, substituting one of its hydrophilic poly-ethylene oxide (PEO) blocks with a (t)ert-butyl terminus added to the hydrophobic poly-propylene oxide (PPO) block yields a di-block compound (PEO-PPOt) that interacts better with the cell membrane lipid bi-layer and exhibits greater cellular protection than the gold standard tri-block P188 (PEO75-PPO30-PEO75). For this study, we custom-made three different new di-blocks (PEO113-PPO10t, PEO226-PPO18t and PEO113-PPO20t) to systemically examine the effects of the length of each polymer block on cellular protection in comparison to P188. Cellular protection was assessed by cell viability, lactate dehydrogenase release, and uptake of FM1-43 in mouse artery endothelial cells (ECs) following HR injury. We found that di-block CCMS were able to provide the same or better EC protection than P188. Our study provides the first direct evidence that custom-made di-block CCMS can be superior to P188 in improving EC membrane protection, raising their potential in treating cardiac reperfusion injury. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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Review

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22 pages, 2034 KiB  
Review
Neuroprotection Is in the Air—Inhaled Gases on Their Way to the Neurons
by Stefanie Scheid, Ulrich Goebel and Felix Ulbrich
Cells 2023, 12(20), 2480; https://doi.org/10.3390/cells12202480 - 18 Oct 2023
Cited by 3 | Viewed by 1429
Abstract
Cerebral injury is a leading cause of long-term disability and mortality. Common causes include major cardiovascular events, such as cardiac arrest, ischemic stroke, and subarachnoid hemorrhage, traumatic brain injury, and neurodegenerative as well as neuroinflammatory disorders. Despite improvements in pharmacological and interventional treatment [...] Read more.
Cerebral injury is a leading cause of long-term disability and mortality. Common causes include major cardiovascular events, such as cardiac arrest, ischemic stroke, and subarachnoid hemorrhage, traumatic brain injury, and neurodegenerative as well as neuroinflammatory disorders. Despite improvements in pharmacological and interventional treatment options, due to the brain’s limited regeneration potential, survival is often associated with the impairment of crucial functions that lead to occupational inability and enormous economic burden. For decades, researchers have therefore been investigating adjuvant therapeutic options to alleviate neuronal cell death. Although promising in preclinical studies, a huge variety of drugs thought to provide neuroprotective effects failed in clinical trials. However, utilizing medical gases, noble gases, and gaseous molecules as supportive treatment options may offer new perspectives for patients suffering neuronal damage. This review provides an overview of current research, potentials and mechanisms of these substances as a promising therapeutic alternative for the treatment of cerebral injury. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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24 pages, 7779 KiB  
Review
Sex Differences in Therapies against Myocardial Ischemia-Reperfusion Injury: From Basic Science to Clinical Perspectives
by Lejla Medzikovic, Tara Azem, Wasila Sun, Parmis Rejali, Leana Esdin, Shadie Rahman, Ateyeh Dehghanitafti, Laila Aryan and Mansoureh Eghbali
Cells 2023, 12(16), 2077; https://doi.org/10.3390/cells12162077 - 16 Aug 2023
Cited by 3 | Viewed by 1777
Abstract
Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading [...] Read more.
Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading to ischemia-reperfusion injury (IRI). While experimental studies overwhelmingly demonstrate that females experience greater functional recovery from MI and decreased severity in the underlying pathophysiological mechanisms, the outcomes of MI with subsequent reperfusion therapy, which is the clinical correlate of myocardial IRI, are generally poorer for women compared with men. Distressingly, women are also reported to benefit less from current guideline-based therapies compared with men. These seemingly contradicting outcomes between experimental and clinical studies show a need for further investigation of sex-based differences in disease pathophysiology, treatment response, and a sex-specific approach in the development of novel therapeutic methods against myocardial IRI. In this literature review, we summarize the current knowledge on sex differences in the underlying pathophysiological mechanisms of myocardial IRI, including the roles of sex hormones and sex chromosomes. Furthermore, we address sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of current drugs prescribed to limit myocardial IRI. Lastly, we highlight ongoing clinical trials assessing novel pharmacological treatments against myocardial IRI and sex differences that may underlie the efficacy of these new therapeutic approaches. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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17 pages, 1699 KiB  
Review
Targeting Soluble Guanylyl Cyclase during Ischemia and Reperfusion
by Eric H. Mace, Melissa J. Kimlinger, Frederic T. Billings IV and Marcos G. Lopez
Cells 2023, 12(14), 1903; https://doi.org/10.3390/cells12141903 - 21 Jul 2023
Cited by 1 | Viewed by 1825
Abstract
Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to [...] Read more.
Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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31 pages, 1713 KiB  
Review
Pharmacological Cardioprotection against Ischemia Reperfusion Injury—The Search for a Clinical Effective Therapy
by Qian Wang, Coert J. Zuurbier, Ragnar Huhn, Carolin Torregroza, Markus W. Hollmann, Benedikt Preckel, Charissa E. van den Brom and Nina C. Weber
Cells 2023, 12(10), 1432; https://doi.org/10.3390/cells12101432 - 20 May 2023
Cited by 9 | Viewed by 2125
Abstract
Pharmacological conditioning aims to protect the heart from myocardial ischemia-reperfusion injury (IRI). Despite extensive research in this area, today, a significant gap remains between experimental findings and clinical practice. This review provides an update on recent developments in pharmacological conditioning in the experimental [...] Read more.
Pharmacological conditioning aims to protect the heart from myocardial ischemia-reperfusion injury (IRI). Despite extensive research in this area, today, a significant gap remains between experimental findings and clinical practice. This review provides an update on recent developments in pharmacological conditioning in the experimental setting and summarizes the clinical evidence of these cardioprotective strategies in the perioperative setting. We start describing the crucial cellular processes during ischemia and reperfusion that drive acute IRI through changes in critical compounds (∆GATP, Na+, Ca2+, pH, glycogen, succinate, glucose-6-phosphate, mitoHKII, acylcarnitines, BH4, and NAD+). These compounds all precipitate common end-effector mechanisms of IRI, such as reactive oxygen species (ROS) generation, Ca2+ overload, and mitochondrial permeability transition pore opening (mPTP). We further discuss novel promising interventions targeting these processes, with emphasis on cardiomyocytes and the endothelium. The limited translatability from basic research to clinical practice is likely due to the lack of comorbidities, comedications, and peri-operative treatments in preclinical animal models, employing only monotherapy/monointervention, and the use of no-flow (always in preclinical models) versus low-flow ischemia (often in humans). Future research should focus on improved matching between preclinical models and clinical reality, and on aligning multitarget therapy with optimized dosing and timing towards the human condition. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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21 pages, 1366 KiB  
Review
Microvascular Leakage as Therapeutic Target for Ischemia and Reperfusion Injury
by Jan Andreas Kloka, Benjamin Friedrichson, Petra Wülfroth, Rainer Henning and Kai Zacharowski
Cells 2023, 12(10), 1345; https://doi.org/10.3390/cells12101345 - 09 May 2023
Cited by 5 | Viewed by 1876
Abstract
Reperfusion injury is a very common complication of various indicated therapies such as the re-opening of vessels in the myocardium or brain as well as reflow in hemodynamic shutdown (cardiac arrest, severe trauma, aortic cross-clamping). The treatment and prevention of reperfusion injury has [...] Read more.
Reperfusion injury is a very common complication of various indicated therapies such as the re-opening of vessels in the myocardium or brain as well as reflow in hemodynamic shutdown (cardiac arrest, severe trauma, aortic cross-clamping). The treatment and prevention of reperfusion injury has therefore been a topic of immense interest in terms of mechanistic understanding, the exploration of interventions in animal models and in the clinical setting in major prospective studies. While a wealth of encouraging results has been obtained in the lab, the translation into clinical success has met with mixed outcomes at best. Considering the still very high medical need, progress continues to be urgently needed. Multi-target approaches rationally linking interference with pathophysiological pathways as well as a renewed focus on aspects of microvascular dysfunction, especially on the role of microvascular leakage, are likely to provide new insights. Full article
(This article belongs to the Special Issue New Developments in Pharmacological Drug Discovery for Cardio- and Neuroprotection against Ischemia/Reperfusion Injury)
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