Evidence and opportunities of hypothermia in acute ischemic stroke: Clinical trials of systemic versus selective hypothermia

Huber, Mitchell; Ding, Yuchuan

doi:10.4103/bc.bc_25_19

Cited by 22 publications

(9 citation statements)

References 48 publications

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“…Hypothermia therapy has been found to exert neuroprotective effects in many neurological diseases, such as stroke, traumatic brain injury, intracranial pressure elevation, and neonatal encephalopathy (Huber et al, 2019;Sun et al, 2019). In light of this, there is now growing evidence demonstrating that NT(8-13) analogs induce regulated reduction of body and brain temperatures through activation of the NTS1 receptor subtype (Liu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Mild hypothermia (32-35 • C) has been proven to exert neuroprotective effects in a variety of neurological conditions, such as global ischemia after cardiac arrest, hypoxic-ischemic encephalopathy, ischemic stroke, and traumatic injury (Huber et al, 2019). Indeed, therapeutic cooling has been described to counteract many of the deleterious processes occurring in the setting of cerebral ischemia, including neuroinflammation, free radical production, excitotoxicity, and apoptosis, as well as blood-brain barrier disruption (Sun et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

et al. 2020

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Therapeutic hypothermia represents a brain-protective strategy for multiple emergency situations, such as stroke or traumatic injury. Neurotensin (NT), which exerts its effects through activation of two G protein-coupled receptors, namely NTS1 and NTS2, induces a strong and long-lasting decrease in core body temperature after its central administration. Growing evidence demonstrates that NTS1 is the receptor subtype mediating the hypothermic action of NT. As such, potent NTS1 agonists designed on the basis of the minimal C-terminal NT(8-13) bioactive fragment have been shown to produce mild hypothermia and exert neuroprotective effects under various clinically relevant conditions. The high susceptibility of NT(8-13) to protease degradation (half-life <2 min) represents, however, a serious limitation for its use in pharmacological therapy. In light of this, we report here a structure-activity relationship study in which pairs of NT(8-13) analogs have been developed, based on the incorporation of a reduced Lys 8-Lys 9 bond. To further stabilize the peptide bonds, a panel of backbone modifications was also inserted along the peptide sequence, including Sip 10 , D-Trp 11 , Dmt 11 , Tle 12 , and TMSAla 13. Our results revealed that the combination of appropriate chemical modifications leads to compounds exhibiting improved resistance to proteolytic cleavages (>24 h; 16). Among them, the NT(8-13) analogs harboring the reduced amine bond combined with the unnatural amino acids TMSAla 13 (4) and Sip 10 (6) or the di-substitution Lys 11-TMSAla 13 (12), D-Trp 11-TMSAla 13 (14), and Dmt 11-Tle 12 (16) produced sustained hypothermic effects (−3 • C for at least 1 h). Importantly, we observed that hypothermia was mainly driven by the increased stability of the NT(8-13) derivatives, instead of the high binding-affinity at NTS1. Altogether, these results reveal the importance of the reduced amine bond in optimizing the metabolic properties of the NT(8-13) peptide and support the development of stable NTS1 agonists as first drug candidate in neuroprotective hypothermia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

et al. 2020

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“…These functional neural networks [60] can be found in the intact hemisphere. Changes within the ischemic penumbra [61] start relatively quickly after stroke, providing the first symptoms of early recovery. The surviving neurons after stroke [62] undergo structural and functional remodeling.…”

Section: Neuroplasticitymentioning

confidence: 99%

Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke

Onose

Anghelescu

Blendea

et al. 2022

IJMS

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BACKGROUND: Cerebral circulation delivers the blood flow to the brain through a dedicated network of sanguine vessels. A healthy human brain can regulate cerebral blood flow (CBF) according to any physiological or pathological challenges. The brain is protected by its self-regulatory mechanisms, which are dependent on neuronal and support cellular populations, including endothelial ones, as well as metabolic, and even myogenic factors. OBJECTIVES: Accumulating data suggest that “non-pharmacological” approaches might provide new opportunities for stroke therapy, such as electro-/acupuncture, hyperbaric oxygen therapy, hypothermia/cooling, photobiomodulation, therapeutic gases, transcranial direct current stimulations, or transcranial magnetic stimulations. We reviewed the recent data on the mechanisms and clinical implications of these non-pharmaceutical treatments. METHODS: To present the state-of-the-art for currently available non-invasive, non-pharmacological-related interventions in acute ischemic stroke, we accomplished this synthetic and systematic literature review based on the Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses (PRISMA). RESULTS: The initial number of obtained articles was 313. After fulfilling the five steps in the filtering/selection methodology, 54 fully eligible papers were selected for synthetic review. We enhanced our documentation with other bibliographic resources connected to our subject, identified in the literature within a non-standardized search, to fill the knowledge gaps. Fifteen clinical trials were also identified. DISCUSSION: Non-invasive, non-pharmacological therapeutic/rehabilitative interventions for acute ischemic stroke are mainly holistic therapies. Therefore, most of them are not yet routinely used in clinical practice, despite some possible beneficial effects, which have yet to be supplementarily proven in more related studies. Moreover, few of the identified clinical trials are already completed and most do not have final results. CONCLUSIONS: This review synthesizes the current findings on acute ischemic stroke therapeutic/rehabilitative interventions, described as non-invasive and non-pharmacological.

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“…However, the available clinical evidence shows rather neutral brain effects and negative systemic complications in humans (Schneider et al, 2017;Wu et al, 2020). Global hypothermia induces multiple and severe systemic side effects, such as shivering, cardiac arrhythmias, vasoconstriction, pneumonia, kidney dysfunction, diffuse coagulopathy, and electrolyte imbalances (Huber et al, 2019;Kuczynski et al, 2020). Moreover, the neuroprotective effects of TH are largely time-sensitive (early hypothermia is protective, late is deleterious) (Kawamura et al, 2005;Huber et al, 2019) and depend on magnitude (mild or strong), duration of application, site of application (local on brain versus systemic application), and inherent characteristics of the organism (age and comorbidities, rodent vs. human differences) (Wu et al, 2020).…”

Section: What Do We Learn From the Application Of Therapeutic Hypothermia In Stroke? (Comparing A Positive And A Negative Translational Smentioning

confidence: 99%

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

et al. 2021

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Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

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Evidence and opportunities of hypothermia in acute ischemic stroke: Clinical trials of systemic versus selective hypothermia

Cited by 22 publications

References 48 publications

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

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