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9 pages, 2199 KiB

Open AccessCommunication

Ischemic Post-Conditioning in a Rat Model of Asphyxial Cardiac Arrest

by Matthew B. Barajas, Takuro Oyama, Masakazu Shiota, Zhu Li, Maximillian Zaum, Ilija Zecevic and Matthias L. Riess

Cells 2024, 13(12), 1047; https://doi.org/10.3390/cells13121047 - 17 Jun 2024

Viewed by 822

Abstract

Background: Ischemic post-conditioning (IPoC) has been shown to improve outcomes in limited pre-clinical models. As down-time is often unknown, this technique needs to be investigated over a range of scenarios. As this tool limits reperfusion injury, there may be limited benefit or even [...] Read more.

Background: Ischemic post-conditioning (IPoC) has been shown to improve outcomes in limited pre-clinical models. As down-time is often unknown, this technique needs to be investigated over a range of scenarios. As this tool limits reperfusion injury, there may be limited benefit or even harm after short arrest and limited ischemia-reperfusion injury. Methods: Eighteen male Wistar rats underwent 7 min of asphyxial arrest. Animals randomized to IPoC received a 20 s pause followed by 20 s of compressions, repeated four times, initiated 40 s into cardiopulmonary resuscitation. If return of spontaneous circulation (ROSC) was achieved, epinephrine was titrated to mean arterial pressure (MAP) of 70 mmHg. Data were analyzed using t-test or Mann–Whitney test. Significance set at p ≤ 0.05. Results: The rate of ROSC was equivalent in both groups, 88%. There was no statistically significant difference in time to ROSC, epinephrine required post ROSC, carotid flow, or peak lactate at any timepoint. There was a significantly elevated MAP with IPoC, 90.7 mmHg (SD 13.9), as compared to standard CPR, 76.7 mmHg (8.5), 2 h after ROSC, p = 0.03. Conclusions: IPoC demonstrated no harm in a model of short arrest using a new arrest etiology for CPR based IPoC intervention in a rat model. 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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23 pages, 4445 KiB

Open AccessArticle

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 - 5 Jun 2023

Cited by 1 | Viewed by 2796

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

Open AccessArticle

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 1541

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

Open AccessReview

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 5 | Viewed by 2212

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

Open AccessReview

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 9 | Viewed by 2625

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

Open AccessReview

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 3 | Viewed by 2907

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

Open AccessReview

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 17 | Viewed by 3370

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 (∆G_ATP, 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

Open AccessReview

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 - 9 May 2023

Cited by 6 | Viewed by 2509

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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