Heart Attacks Release Toxin That Damages Brain Function

 Have your competent? doctor deliver an EXACT POROTOCOL THAT FIXES THIS! 

Will require ensuring the research continues to EXACTLY providing a protocol!

Heart Attacks Release Toxin That Damages Brain Function

Summary: Researchers cracked a critical hidden mechanism behind the “heart-brain axis,” revealing how a heart attack physically reshapes brain function to cause depression, anxiety, and cognitive decline. The research demonstrates that following a cardiac event, a highly reactive, toxic byproduct called methylglyoxal (MG) surges into the bloodstream and aggregates inside mood and memory centers of the brain.This discovery explains the biological link between cardiac stress and post-stroke psychiatric conditions while introducing an innovative peptide therapy designed to trap the toxin and shield vulnerable brain tissue.

Key Facts

• The Heart-Brain Axis: Neurological and cognitive conditions that manifest after a heart attack are directly fueled by specific, cascading molecular alterations kicked off by structural damage to heart tissue.
• The Toxic Byproduct Accumulation: Following a myocardial infarction, the human body enters a state of high metabolic stress characterized by oxygen drops and systemic inflammation. This hostile shift causes methylglyoxal (MG)—a reactive molecule famously studied in metabolic disorders like diabetes—to spike in the blood and pool in brain zones governing cognition and emotion.
• The Psychological Trap: Individuals recovering from a heart attack experience depression and anxiety at a rate up to three times higher than the general population. Alarmingly, cardiac patients who develop these mental health conditions are up to 2.7 times more likely to suffer a subsequent, fatal heart attack or death.
• Unveiling Chronic Risks: By establishing methylglyoxal as a primary instigator of cellular brain damage and localized chronic neuroinflammation, this study uncovers a distinct biological pathway explaining why a heart attack spikes long-term dementia risks.
• The MG-Trapping Peptide: Moving rapidly from raw discovery to targeted clinical therapeutics, the University of Ottawa team has engineered a unique peptide therapeutic engineered to physically trap methylglyoxal before it can damage neural cells.
• Dual-System Protection: Senior author Dr. Erik Suuronen notes that if forthcoming clinical trials prove successful, this trapping therapy will do more than preserve brain health; by alleviating depression and anxiety, it could drastically lower the 2.7x risk of repeat cardiac mortality, filling a massive unmet clinical gap.
• Source: University of Ottawa

A new study led by a team from the University of Ottawa takes a major step forward in understanding how a heart attack can dramatically reshape brain function and trigger neurological effects, from depression and anxiety to different types of cognitive decline.

This ‘heart-brain axis’ concept suggests that neurological conditions following a heart attack could be driven in part by molecular changes set in motion by damage to the heart. While there are many factors and signaling pathways involved in heart-brain interactions, this newly published research suggests that a toxic byproduct produced by the body plays a major role in the brain following a heart attack.

Brain inflammation after cardiac events

At the center of the discovery is methylglyoxal (MG), a highly reactive molecule, which surges in the bloodstream and accumulates in the brain following a heart attack. Following a heart attack, the body enters a state of stress—oxygen drops, inflammation rises, metabolism shifts—causing MG levels to surge in the bloodstream and then accumulate in the brain in specific brain regions linked to mood and cognition.

The occurrence of depression and anxiety in heart attack patients is up to three times higher than the general population, with patients who suffer depression or anxiety may be up to 2.7 times more likely to experience another heart attack or death.

Charting new territory in brain-heart connection

Published in the journal Advanced Sciences, this finding could potentially transform recovery and long-term outcomes for millions as it reshapes how scientists understand long-term risks after myocardial infarction and explain why emotional and cognitive disorders are so common after cardiac events.  

“Methylglyoxal has been widely studied for its role in metabolic diseases, including diabetes, but much less is known about its function in other diseases. In a previous study, we discovered that methylglyoxal was produced by dying heart tissue after a heart attack (…) based on this evidence, we predicted that methylglyoxal in the blood would target other organs and tissues, including the brain—and this is what we did indeed observe,” says senior author Dr. Erik Suuronen, a Full Professor in the Faculty of Medicine’s Department of Surgery, a scientist in the Division of Cardiac Surgery and director of its BEaTs Research Program at the University of Ottawa Heart Institute.

Moving from discovery toward therapy

The team’s discoveries raise important questions about neurodegenerative disease as chronic inflammation and cellular damage in the brain are key drivers of cognitive conditions like dementia.

By identifying methylglyoxal as a trigger, this research suggests a new pathway through which heart attacks could increase long-term neurological risk. Having identified methylglyoxal as a potential target for treating neurological disorders after a heart attack, the next step is to explore how MG-driven inflammation leads to neuron death and mental health conditions.

Importantly, the research team has already developed a peptide therapeutic that can trap methylglyoxal and prevent it from damaging cells.

“This therapy will soon be tested to see if it can protect the brain from damage after a heart attack,” says Dr. Suuronen, who believes if successful, such treatments could do more than protect brain function; they could potentially reduce the risk of future cardiac events.

“Given the increased risk of subsequent heart attacks or death in heart attack patients who experience depression or anxiety, being able to alleviate these conditions could reduce subsequent major cardiac events and improve the lives of countless patients, filling an urgent unmet clinical need,” Dr. Suuronen adds.

Key Questions Answered:

Q: Why are people who survive a heart attack suddenly at a drastically higher risk for severe depression and dementia?

A: For decades, it was assumed to be purely psychological trauma, but this study proves a major physical, toxic link. When heart tissue dies during a heart attack, it pumps out a highly reactive, toxic byproduct called methylglyoxal (MG). This toxin travels through the bloodstream and pools inside the brain’s emotional and memory centers, triggering cellular damage and inflammation that degrades brain health.

Q: How does having post-heart attack anxiety make a patient nearly three times more likely to die from a second cardiac event?

A: The heart-brain axis is a two-way street. Once the toxic MG surge damages brain cells and triggers chronic mental health struggles, those psychiatric conditions feed straight back into your cardiovascular system. The persistent stress of anxiety and depression strains the heart, raising the likelihood of a secondary, fatal heart attack or death by 2.7 times.

Q: How does a simple “peptide trap” work to save a heart attack survivor’s brain from decay?

A: Think of it like a molecular sponge. The University of Ottawa team developed a custom peptide therapeutic specifically engineered to recognize, latch onto, and neutralize methylglyoxal in the body. By trapping this molecule before it can infiltrate the central nervous system, the drug prevents it from damaging brain tissue, shielding both your mental health and your long-term cognitive survival.

Editorial Notes:

• This article was edited by a Neuroscience News editor.
• Journal paper reviewed in full.
• Additional context added by our staff.

About this neurology research news

Author: Paul Logothetis
Source: University of Ottawa
Contact: Paul Logothetis – University of Ottawa
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Methylglyoxal Accumulation is Associated with Brain Inflammation after Myocardial Infarction with Sex and Regional Differences” by Ramis Ileri, Xixi Guo, Erik J. Suuronen. Advanced Science
DOI:10.1002/advs.202522584

Injectable nanomaterial reduces secondary brain injury after ischemic stroke

I can almost guarantee your doctor and hospital will KNOW NOTHING AND DO NOTHING! 

No human research will occur; nothing will be done! That is how fucking incompetent the whole stroke medical world is. Hopefully comeuppance will hit them all with a stroke. And they can regret their incompetence in not solving stroke to 100% recovery!

Al this incompetence is a result of NO leadership firing the incompetent persons!

Injectable nanomaterial reduces secondary brain injury after ischemic stroke

When a person suffers a stroke, physicians must restore blood flow to the brain as quickly as possible to save their life. But, ironically, that life-saving rush of blood can also trigger a second wave of damage - killing brain cells, fueling inflammation and increasing the odds of long-term disability.

Now, Northwestern University scientists have developed an injectable regenerative nanomaterial that helps protect the brain during this vulnerable window.

In a new preclinical study, the team delivered a single intravenous dose, immediately after restoring blood flow, in a mouse model of ischemic stroke, the most common type of stroke. The therapy successfully crossed the blood-brain barrier - a major challenge for most drugs - to reach and repair brain tissue. The material significantly reduced brain damage and showed no signs of side effects or organ toxicity.

Published Jan. 7 in the journal Neurotherapeutics, the findings suggest the new therapy could eventually complement existing stroke treatments by limiting secondary brain injury and supporting recovery.

Current clinical approaches are entirely focused on blood flow restoration. Any treatment that facilitates neuronal recovery and minimizes injury would be very powerful, but that holy grail doesn't yet exist. This study is promising because it's leading us down a pathway to develop these technologies and therapeutics for this unmet need."

Dr. Ayush Batra, associate professor, neurology (neurocritical care) and pathology at Northwestern University Feinberg School of Medicine, co-director of the NeuroVascular Inflammation Laboratory at Northwestern and a neurocritical care physician with Northwestern Medicine

The injectable therapy is based on supramolecular therapeutic peptides (STPs), a platform developed by Northwestern's Samuel I. Stupp. A study published in 2021 in the journal Science demonstrated the use of an STP technology - nicknamed "dancing molecules" - because of the highly dynamic nature of its therapeutic agents that could reverse paralysis and repair tissue in mice after a single injection at the site of severe spinal cord injury. The new study found scientists can administer similar dynamic assemblies of molecules intravenously, without requiring surgery or an invasive injection directly into the brain.

"One of the most promising aspects of this study is that we were able to show this therapeutic technology, which has shown incredible promise in spinal cord injury, can now begin to be applied in a stroke model and that it can be delivered systemically," said Stupp, co-corresponding author and Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern. "This systemic delivery mechanism and the ability to cross the blood-brain barrier is a significant advance that could also be useful in treating traumatic brain injuries and neurodegenerative diseases such as ALS."

Stupp also is founding director of the Center for Regenerative Nanomedicine. He has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine.

Study mimicked real-world stroke treatment

Acute ischemic stroke, which accounts for 80% of all strokes in the U.S., is a devastating condition and is one of the leading causes of morbidity and mortality worldwide, Batra said. Ischemic strokes occur when a clot blocks blood flow to the brain. Physicians reopen the vessel by administering "clot-busting" drugs or using devices to surgically remove the clot.

Severe strokes can lead to permanent, significant disability that affects a patient's quality of life and their ability to return to work and engage with their family and society.

"It has not only a significant personal and emotional burden on patients, but also a financial burden on families and communities," he said. "Reducing this level of disability with a therapy that could potentially help in restoring function and minimizing injury would really have a powerful long-term impact."

The findings are highly relevant for future clinical applications because the scientists tested the approach in a mouse model that closely mimics real-world ischemic stroke treatment, Batra said. They first blocked blood flow to simulate a major ischemic stroke and then restored it (a process called reperfusion), just as doctors restore blood flow acutely for ischemic stroke patients. 

The scientists monitored the mice for seven days and didn't observe any significant side effects or biocompatibility issues such as toxicity or immune system rejection. They used advanced imaging techniques, such as real-time intravital intracranial microscopy seen in this video, to confirm the therapy localized to the stroke injury site. Compared to untreated mice, those treated with the "dancing molecules" had significantly less brain tissue damage, reduced signs of inflammation and reduced signs of excessive, damaging immune response.

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Stupp said the therapy has pro-regenerative and anti-inflammatory properties, both of which contributed to the positive results.

"You get an accumulation of harmful molecules once the blockage occurs and then suddenly you remove the clot and all those 'bad actors' get released into the bloodstream, where they cause additional damage," Stupp said. "But the dancing molecules carry with them some anti-inflammatory activity to counteract these effects and at the same time help repair neural networks." 

Dynamic 'dancing molecules' can be dialed down in concentration

The secret behind Stupp's "dancing molecules" breakthrough therapeutic is tuning the collective motion of molecules, so they can find and properly engage constantly moving cellular receptors. The treatment sends signals that encourage nerve cells to repair themselves. For example, it can help nerve fibers (called axons) grow again and reconnect with other nerve cells, restoring lost communication. This process is called plasticity, which means the brain and spinal cord can adapt and rebuild connections after injury. 

In previous studies, scientists injected the dancing molecules as a liquid, and when used to treat spinal cord injury, the therapy immediately gels into a complex network of nanofibers that mimic the dense, extracellular matrix of the spinal cord. By matching the matrix's structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.

In the new study, the scientists dialed down the concentration of supramolecular peptide assemblies to prevent possible clotting as the therapy enters the bloodstream. Smaller aggregates of peptides easily crossed the blood-brain barrier. Once enough molecules cross, larger nanofiber assemblies can form in brain tissue to produce a more potent therapeutic effect, Stupp said.

"We chose for this stroke study one of the most dynamic therapies we had in terms of its molecular structure so that supramolecular assemblies would have a better probability of crossing the blood-brain barrier," Stupp said. 

Optimizing therapeutic targeting

The fact that seemingly effective therapies cannot cross the blood-brain barrier has plagued the neuroscience field for decades, Batra said. This new therapy could change that.

When a physician acutely restores blood flow to a region of the brain in a stroke patient, the blood-brain barrier permeability is locally increased, naturally creating a transient opening and opportunity for therapeutic intervention, Batra said.

"Add to that a dynamic peptide that is able to cross more readily, and you're really optimizing the chances that your therapy is going where you want it to go," Batra said. 

Next steps

Further studies will need to assess whether this treatment can support longer-term, functional recovery, Batra said. For instance, many stroke patients suffer from significant cognitive decline throughout the subsequent year after a stroke. The new therapy is primed to address that secondary injury, Batra said, but the studies will require a longer follow-up period and more sophisticated behavioral testing. 

In addition, the team is interested in testing whether additional regenerative signals could be incorporated into the therapeutic peptides to produce even better results.

The study is titled, "Toward Development of a Dynamic Supramolecular Peptide Therapy for Acute Ischemic Stroke." Graduate student Zijun Gao and postdoctoral researcher Luisa Andrade da Silva are co-first authors of the paper. 

Funding for this study was primarily provided by the SQI Synthesizer Grant Program at the Center for Regenerative Nanomedicine.

Source:

Northwestern University

Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke -recruiting

 

Your competent? doctor has been working on peptides for over a decade, right? Oh NO, INCOMPETENCE REIGNED AND NOTHING WAS DONE, CORRECT?

Let's see EXACTLY HOW LONG AND IN WHAT YOUR DOCTOR IS INCOMPETENT!

peptide (16 posts to January 2012)

nerinetide (10 posts to February 2020)

Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial

 November 2024

Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke  January 2021 

Apolipoprotein E mimetic peptide, CN-105, improves outcomes in ischemic stroke

March 2017

The latest here:

Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke

ClinicalTrials.gov IDNCT05691244

SponsorPharmazz, Inc.

Information Provided byAnil Gulati, MD, PhD

Study Start (Actual)2025-07-24

Primary Completion (Estimated) 2026-09

Study Completion (Estimated)2026-11

Enrollment (Estimated)514

Study TypeInterventional

Last Update Posted2025-10-16

Study Overview

Brief Summary

Extensive research is being conducted in search of neuroprotective agents for possible use in the acute phase of stroke and agents that can be used for neurorepair in later stages of stroke. Several trials have been conducted and are in progress using different pharmacological agents, but none of the studies involve the stimulation of ETB receptors to treat cerebral ischemic stroke. Sovateltide (IRL-1620, PMZ-1620) has been effective in animal models of cerebral ischemic stroke. Its safety and tolerability have been demonstrated in a human phase I study with 7 subjects. Clinical phase II and III results indicate that sovateltide is a novel, first-in-class, highly effective drug candidate for treating cerebral ischemic stroke. Safety and significant efficacy in improving the National Institutes of Health Stroke Scale (NIHSS), Modified Rankin scale (mRS), and Barthel index (BI) obtained in phase II and III studies in patients with cerebral ischemic stroke in India are convincing and encouraged us to investigate its safety and efficacy in cerebral ischemic stroke patients in the United States. Therefore, the plan is to conduct a phase III clinical study to evaluate the safety and efficacy of sovateltide therapy along with standard of care in patients of acute ischemic stroke.

To learn more, visitClinicalTrials.gov

Advances in clinical studies of peptide drugs in stroke disease

 Your competent? doctor has been working on peptides for over a decade, right? Oh NO, INCOMPETENCE REIGNED AND NOTHING WAS DONE, CORRECT?

Let's see EXACTLY HOW LONG AND IN WHAT YOUR DOCTOR IS INCOMPETENT!

peptide (16 posts to January 2012)

nerinetide (10 posts to February 2020)

Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial

 November 2024

Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke  January 2021 

Apolipoprotein E mimetic peptide, CN-105, improves outcomes in ischemic stroke

March 2017

The latest here:

Advances in clinical studies of peptide drugs in stroke disease

Author links open overlay panel, , , , 

https://doi.org/10.1016/j.bbadis.2025.167970Get rights and content

Highlights

• •
  Peptide drugs exhibit tremendous potential in stroke treatment, characterized by high specificity, and low toxicity.
• •
  Multiple peptide drugs (such as CN-105, Nerinetide, and Sovateltide) show promising therapeutic prospects in clinical trials for stroke treatment.
• •
  Peptide drugs still face challenges in stability, delivery, and bioavailability.
• •
  Peptide drugs represent an innovative frontier in stroke treatment, offering potential new therapeutic options for patients.

Abstract

Stroke remains a leading cause of death and disability globally, with limited treatment options currently available. Fortunately, peptide drugs have emerged as promising candidates for treating central nervous system disorders, including stroke. They offer high specificity, low toxicity, and efficient blood-brain barrier penetration, demonstrating significant therapeutic potential. This review systematically introduces several promising peptide drugs, analyzing their mechanisms, therapeutic efficacy in clinical trials, and potential applications. It also addresses critical challenges in peptide drug development for stroke therapy, such as optimizing dosing strategies, enhancing stability, and improving delivery systems. The analysis of current clinical evidence suggests that peptide-based therapeutics represent a promising frontier in stroke treatment, potentially offering new therapeutic options for patients. This comprehensive review not only highlights the current status of peptide drug development but also provides insights into future directions for advancing stroke therapy.

Introduction

Stroke threatens human health and can lead to death and long-term disability [1]. The World Stroke Organization (WSO) stated that stroke is the second reason cause of death globally and the third reason cause of death and disability in its 2022 Global Stroke Fact Sheet [2]. And in 2019, the estimated global cost of stroke exceeded $891 billion, accounting for 1.12 % of the worldwide GDP [2]. The American Heart Association (AHA) also indicated that the prevalence of stroke in the United States is estimated to be 3.3 %, with approximately 9.4 million Americans aged 20 and older self-reporting a history of stroke in its 2023 Stroke Statistics Report [3]. One study suggests an additional 3.4 million adults aged 18 and older would have a stroke in the U.S. by 2030, an increase of 20.5 % from 2012 [2]. The mechanisms of neurological injury in stroke are complex, including cellular mitochondrial dysfunction [4], neuroinflammation [5], excitotoxicity [6], oxidative stress [7], and apoptosis [8]. Current stroke management strategies predominantly rely on time-sensitive interventional approaches, including intravenous thrombolysis (IVT), intra-arterial thrombolysis (IAT), and endovascular thrombectomy (EVT). However, a critically narrow therapeutic window significantly constrains their clinical efficacy [9,10]. That means only a small fraction of stroke patients could get immediate treatment, while the overwhelming majority are precluded from these therapies. This clinical landscape shows the pressing necessity for the development of innovative neuroprotective strategies that can expand the therapeutic window. Consequently, the exploration of targeted neuroprotective agents has become a research priority to mitigate acute neurological damage and provide other effective programs for stroke treatment [11]. This review briefly introduces peptide drugs and summarizes the progress of clinical studies of peptide drugs as neuroprotective agents in stroke.

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Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

 So with further research suggested will your competent? doctor and hospital ensure it gets done? Oh, you don't have a functioning stroke doctor or hospital that even knows about this, much less get more research done?

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial

Francisco Hernández-Bernal^1,2†‡Donner Estenoz-García^3‡Juan H. Gutiérrez-Ronquillo^4‡Yenima Martín-Bauta^1‡Karen Catasús-Álvarez^1‡Mario Gutiérrez-Castillo^4‡Marbelys Guevara-Rodríguez^4‡Aliuska Castro-Jeréz^5‡Yoandra Fuentes-González^5‡Yulemis Pinto-Cruz^3‡Carmen Valenzuela-Silva^6‡Verena L. Muzio-González^1‡Héctor Pérez-Saad^7‡Nelvys Subirós-Martínez^7‡Gerardo E. Guillén-Nieto^8,9‡Diana Garcia-del-Barco-Herrera^7,9,*†‡ on behalf of the COURAGE (COmbined therapeUtic appRoAch durinG acute strokE) Research Group

• ¹Clinical Trial Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba
• ²Department of Comprehensive General Medicine, Latin American School of Medicine (ELAM), Havana, Cuba
• ³Neurology Department, “Antonio Luaces” Hospital, Ciego de Ávila, Cuba
• ⁴Neurology Department, “Arnaldo Milián” Hospital, Santa Clara, Villa Clara, Cuba
• ⁵Neurology Department, “Celia Sánchez” Hospital, Manzanillo, Gramma, Cuba
• ⁶Institute of Cybernetics, Mathematics, and Physics, Havana, Cuba
• ⁷Neuroprotection Project, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba
• ⁸Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba
• ⁹Department of Physiology, Latin American School of Medicine (ELAM), Havana, Cuba

Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.

Methods: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18–80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.

Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8–11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06–1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03–1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.

Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.

Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

1 Introduction

Ischemic stroke remains an important target for novel preventive and therapeutic strategies. It is estimated that 15 million people worldwide are affected by stroke every year, 5 million of them die and another 5 million of them suffer from long-term disability (1). The global population aged 65 years and over is growing faster than all other age groups, with a concomitant increase in stroke incidence (2). Furthermore, stroke among COVID-19 patients is associated with a significant risk of early mortality (3).

Currently, reperfusion therapy with thrombolytic drugs or endovascular thrombectomy represents the only approved therapeutic approach for acute stroke (4, 5). However, these approaches are associated with a narrow therapeutic window, increased risk of hemorrhagic transformation, and the high cost required to deliver these treatments (6), which limit their suitability for patients (~3%−6%), particularly in low-income countries (7). Moreover, despite treatment, recovery may be incomplete in a significant proportion of patients (8), as the vascular dynamics following recanalization do not invariably reduce tissue injury or reverse functional deficits (9, 10), and there remains scope for additional pharmacological-based neuroprotective interventions in addition to recanalization in acute ischemic stroke.

Considering the strong interdependence of elements in the neurovascular unit (11) and the limitations of neuron-protective strategies in clinical trials (12, 13), the scientific community has moved to combination strategies that seek to enhance endogenous mechanisms of neuroprotection (14). Combined therapies for stroke are likely to be more effective as they simultaneously target multiple levels of the ischemic pathophysiological cascade. However, few clinical trials have been published to date (2).

Molecules that trigger cytoprotective effects can be considered candidates for combined therapies (8). Particularly, a combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) has demonstrated benefit in preclinical contexts by activating pleiotropic endogenous mechanisms of survival and brain protection (15–19). Both molecules cross the blood-brain barrier (20–23), and their receptors are widely distributed in brain tissues (24, 25). EGF and GHRP6 share common properties such as anti-apoptotic (26, 27) and anti-excitotoxic effects (28, 29). In addition, both molecules have independent biological effects. Specifically, EGF promotes neurogenesis and remyelination (30), while GHRP6 induces endogenous neuroprotective factors such as growth hormone and insulin, like growth factor 1 (31).

Previous results of our group demonstrated the therapeutic benefits of this combination in animal models of multiple sclerosis (15), proximal axonopathy mimicking ALS, and focal and global ischemic stroke (16). Later, EGF+GHRP6 combined therapy improved both clinical and pathological aspects as it reduced neurological symptoms and brain infarct volume, preserving neuronal density (17). Additionally, EGF+GHRP6 combined therapy achieved similar results in a preclinical context when compared to therapeutic hypothermia (18). Moreover, both active ingredients exhibited a high safety profile in preclinical and clinical trials (32, 33).

Supported by these data, a phase I/II randomized clinical trial was designed to test the hypothesis that administration of a combined therapy based on rEGF and GHRP6 at two dose levels is safe for acute ischemic stroke (AIS) patients, admitting up to 30% of serious adverse events (SAE) in relation to proven causality. The therapeutic effect was assessed as a secondary endpoint. The current report has been written in compliance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized controlled trials (34, 35).

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