Three major research advances in stroke neuroprotection, worth knowing

*Only for medical professionals to read for reference.
From pre-clinical research to clinical research, see the new progress of AIS neuroprotection research.

Acute ischemic stroke (AIS) is an important cause of death and disability in adults.
The treatment of AIS mainly includes improving cerebral blood circulation and neuroprotective treatment.

Intravenous thrombolysis is currently the most important measure to restore blood flow, but there is a treatment time window [1].

It is the goal pursued by researchers in the field of stroke to seek effective neuroprotective therapies to prevent cerebral ischemia injury and cerebral ischemia-reperfusion injury, and to realize the transformation of benefits from the laboratory to the clinical.

At the recently held International Stroke Conference 2021 (International Stroke Conference 2021), Professor Michael Tymianski from Canada reported on the progress of neuroprotection research.

Figure 1.
The goal of AIS neuroprotection research is to enhance the rigor and reproducibility of preclinical research to test promising neuroprotective interventions and verify them in preclinical models to maximize the possibility of successful human research In November 2016, the National Institute of Nervous System Diseases and Stroke (NINDS) held a seminar titled "Translational Stroke Research: Vision and Opportunity".
Some of the key recommendations at the meeting were to coordinate various Laboratory methods and development of best practices to improve the rigor of preclinical research, match preclinical outcome measurements with relevant human results, motivate team science, verify the findings of independent laboratories, and strengthen data sharing and negative results recording.

To achieve these goals, NINDS funded the Stroke Preclinical Evaluation Network (SPAN), which supports 6 laboratories and a coordination center.

The laboratory will test six hypothetical neuroprotective therapies in parallel, and the coordination center will be responsible for distributing drugs to the laboratory in a random and unknowing manner, statistics and data analysis, and overall supervision of the experiment.

Directly comparing the efficacy of these interventions in multiple laboratories through adaptive design can ensure unbiased and reliable results with a sufficient sample size, and speed up clinical trial preparation [2].

Figure 2.
Stroke experimental model that enhances the rigor of preclinical research is still being explored.
In stroke experimental model research, there are currently more than 25,000 papers published, but the predictive ability of the experimental model is still unclear.

Although many drugs have shown neuroprotective effects in animal models, translational studies from animals to clinics have failed to show the same effect.
This may be the same as animal models that cannot truly represent the state of the disease or the application of drugs in animals and patients.
The difference is related to [3].

There are also differences between different animal models.
Studies have shown that the early gene responses of the middle cerebral artery occlusion model (MCAO) of rats and mice are quite different.

Is the most suitable experimental model of stroke a rat, a mouse, or other experimental animals? Still need to explore further.

Figure 3.
There are differences in early gene responses of MCAO models in rats and mice.
NA-1 can be used as a "positive control" for neuroprotection research.
In the past 50 years, more than 1,000 drugs have been hoped to improve neurological apraxia after AIS.
, But none of them have been recognized by academia.

Therefore, in AIS neuroprotection studies, there has been a lack of suitable "positive controls".

Nerinetide (NA-1) is an eicosopeptide that can interact with postsynaptic density protein 95 (PDS-95).
It stops the production of nitric oxide (NO) in the cell and inhibits cell death signals, thereby reducing The volume of cerebral infarction.

In previous studies, scientists found that it can effectively reduce the ischemia-reperfusion infarct volume in the monkey model and improve its neurological function.

Figure 4.
NA1 mechanism of action The ESCAPE-NA1 study is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the use of the neuroprotective agent NA-1 in AIS patients undergoing endovascular thrombectomy (EVT) Efficacy and safety. The study included 1105 adult AIS patients with great vessel occlusion within the 12-hour treatment window, and they were randomly assigned to the NA-1 group (n=549) and the placebo group (n=556).

The primary endpoint was the proportion of patients with a modified Rankin score (mRS) of 0 to 2 90 days after stroke.

Since alteplase can activate the conversion of plasminogen into plasmin and degrade NA-1, the study was stratified according to whether the patients had received alteplase treatment.

Figure 5.
The results of the ESCAPE-NA1 study design study showed that in all cohorts, there was no statistical difference in the proportion of patients with mRS 0 to 2 in the NA-1 group and the placebo group at 90 days after stroke.

Figure 6.
Analysis of the primary endpoint of the ESCAPE-NA1 study.
But after stratification, the researchers found a very valuable result: In patients who received EVT but not alteplase, compared with placebo, they received NA -1 The proportion of patients who recovered from treatment increased significantly (P=0.
028).

Figure 7.
Results of the stratified analysis of the ESCAPE-NA1 study.
Compared with placebo, NA-1 treatment reduced the risk of death by 40% and the volume of cerebral infarction by 22% in patients who did not use alteplase.

Figure 8.
Results of the stratified analysis of ESCAPE-NA1 study NA-1 is the first drug that has been proven to have neuroprotective effects after AIS.
Professor Michael Tymianski believes that it can be used as a "positive control" for preclinical and clinical neuroprotection studies .

The current ESCAPE-NEXT study in patients not taking alteplase is underway, and it is expected that it will provide more clinical evidence for AIS neuroprotective therapy.

Reference materials: [1] Chinese Medical Association Neurology Branch, Chinese Medical Association Neurology Branch Cerebrovascular Disease Group.
Chinese Acute Ischemic Stroke Diagnosis and Treatment Guide 2018[J].
Chinese Journal of Neurology,2018,51(9) :666-682.
[2]Clinton B Wright,Francesca Bosetti,L Scott Janis,et al.
Organizational Update:NINDS Stroke Research Strategies for Large Vessel Occlusion and Neuroprotection[J].
Stroke.
2021;52(1):e1- e2.
[3]Wang Qun,Wang Yongjun.
Ischemia stroke model selection and preclinical experiment design[J].
Chinese Journal of Stroke,2015,10(2):101-106.