Lessons from Recent Advances in Ischemic Stroke Management and Targeting Kv2.1 for Neuroprotection

Chung-Yang Yeh, Anthony J Schulien, Bradley J Molyneaux, Elias Aizenman, Chung-Yang Yeh, Anthony J Schulien, Bradley J Molyneaux, Elias Aizenman

Abstract

Achieving neuroprotection in ischemic stroke patients has been a multidecade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently, however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We further summarize the results available thus far for nerinetide, a promising neuroprotective agent for stroke treatment. Lastly, we reflect upon aspects of these impactful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We argue that recent changes in the clinical landscape should be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke.

Keywords: Kv2.1; ischemic stroke; nerinetide; neuroprotection; reperfusion.

Conflict of interest statement

E.A. has been awarded a patent for the use of TAT-C1aB as a neuroprotective agent. The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A timeline summary of the clinical trials discussed in this review.
Figure 2
Figure 2
Kv2.1-mediated neuronal cell death and two strategies for neuroprotection. (A) In a healthy neuron, Kv2.1 forms somatodendritic clusters with the ER proteins VAPA/B. (B) After exposure to proapoptotic stimuli, a zinc-mediated phosphorylation cascade leads to enhanced Kv2.1–syntaxin interaction, thus increasing channel insertion at Kv2.1 channel clusters, enhancing potassium efflux, and enabling cell death mechanisms. This process can be halted to provide neuroprotection in several ways, including (C) disrupting Kv2.1–syntaxin binding with TAT-C1aB and (D) dispersing Kv2.1 channel cluster with TAT-DP-2 that interferes with Kv2.1-VAPA/B association. MT: metallothionine; ER: endoplasmic reticulum; ROS: reactive oxygen species.

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Source: PubMed

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