Uncovering the Rosetta Stone: Report from the First Annual Conference on Key Elements in Translating Stroke Therapeutics from Pre-Clinical to Clinical

Bix, Gregory; Fraser, Justin F.; Mack, William J.; Carmichael, S. Thomas; Pérez-Pinzón, Miguel A.; Offner, Halina; Sansing, Lauren H; Bosetti, Francesca; Ayata, Cenk; Pennypacker, Keith R.

doi:10.1007/s12975-018-0628-9

Cited by 12 publications

(13 citation statements)

References 76 publications

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“…Confounders affect the signal-to-noise ratio and thus the sensitivity, specificity, and predictive value of the biomarker [7,8]. It is more likely that multiple biomarkers or panels from "Big Data" could improve precision [8,[12][13][14][15][16]. Big Data in stroke effectively aids in the identification of relevant biomarkers from the myriad possibilities [17].…”

Section: Challenges In Biomarker Utilizationmentioning

confidence: 99%

“…Last, the importance of finding cytoprotective agents in the postendovascular therapy era will require effective biomarkers [8,20]. Neuroprotective agents thus far have failed to effectively translate to clinical application, but appropriately selected biomarkers may revive this effort [13]. Because of these challenges, any proposed biomarker would need to be cross-validated [21].…”

Section: Challenges In Biomarker Utilizationmentioning

confidence: 99%

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Biomarker Application for Precision Medicine in Stroke

Simpkins

Janowski

et al. 2019

Transl. Stroke Res.

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Stroke remains one of the leading causes of long-term disability and mortality despite recent advances in acute thrombolytic therapies. In fact, the global lifetime risk of stroke in adults over the age of 25 is approximately 25%, with 24.9 million cases of ischemic stroke and 18.7 million cases of hemorrhagic stroke reported in 2015. One of the main challenges in developing effective new acute therapeutics and enhanced long-term interventions for stroke recovery is the heterogeneity of stroke, including etiology, comorbidities, and lifestyle factors that uniquely affect each individual stroke survivor. In this comprehensive review, we propose that future biomarker studies can be designed to support precision medicine therapeutic interventions after stroke. The current challenges in defining ideal biomarkers for stroke are highlighted, including consideration of disease course, age, lifestyle factors, and subtypes of stroke. This overview of current clinical trials includes biomarker collection, and concludes with an example of biomarker design for aneurysmal subarachnoid hemorrhage. With the advent of "-omics" studies, neuroimaging, big data, and precision medicine, well-designed stroke biomarker trials will greatly advance the treatment of a disease that affects millions globally every year.

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Section: Challenges In Biomarker Utilizationmentioning

confidence: 99%

Section: Challenges In Biomarker Utilizationmentioning

confidence: 99%

Biomarker Application for Precision Medicine in Stroke

Simpkins

Janowski

et al. 2019

Transl. Stroke Res.

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“…However, a significant portion of those with successful reperfusion may still die or be left with significant neurologic deficits. Thus, interest has been renewed in finding neuroprotective agents that can be used as an adjunct with thrombectomy and clot lysis (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Targeting Parthanatos in Ischemic Stroke

Koehler

Dawson

2021

Front. Neurol.

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Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO). Investigators base their conclusions on the use of nine different PARP inhibitors (19 studies) or PARP1-null mice (7 studies). Several studies indicate a therapeutic window of 4–6 h after MCAO. In young female rats, two studies using two different PARP inhibitors from two labs support a role for parthanatos, whereas two studies from one lab do not support a role in young female PARP1-null mice. In addition to parthanatos, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NF-κB transcription, suppressing matrix metaloproteinase-9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when most did not report behavior outcomes or address the issue of randomization and treatment concealment. Several third-generation PARP inhibitors entered clinical oncology trials without major adverse effects and could be repurposed for stroke. Evaluation in aged animals or animals with comorbidities will be important before moving into clinical stroke trials.

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“…Importantly, early reperfusion is currently the only therapy that has proven to limit infarct size in patients with acute ischaemic stroke [1,3]. However, a substantial number of those patients who receive treatment with tPA and/or thrombectomy in the acute phase do not ever fully recover [4,5]. This reveals the need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy [6].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues—Liraglutide and Semaglutide

Basalay

Davidson

Yellon

2019

Cardiovasc Drugs Ther

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Purpose A substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide. Methods A non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion. Results Liraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39). Conclusion Infarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

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Uncovering the Rosetta Stone: Report from the First Annual Conference on Key Elements in Translating Stroke Therapeutics from Pre-Clinical to Clinical

Cited by 12 publications

References 76 publications

Biomarker Application for Precision Medicine in Stroke

Biomarker Application for Precision Medicine in Stroke

Targeting Parthanatos in Ischemic Stroke

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues—Liraglutide and Semaglutide

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