Are neuroprotective agents necessary for patients with ischemic stroke?

*Only for medical professionals to read for reference.
The research on neuroprotective therapy is progressing slowly, and there is controversy about the efficacy of ischemic stroke.
Should neuroprotective agents be used? Hundreds of "Debates" Big Coffee Show-Neuroprotective Agents Theme Symposium Stroke is the first cause of death and disability in adults in China, and timely thrombolytic therapy is the first choice for stroke [1,2]
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However, due to a variety of factors, the current status of thrombolytic therapy for stroke patients in China is not good, and the proportion of patients who can receive thrombolytic therapy is very small [3]
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Neuroprotective agents are widely used in stroke patients in China.
Some experts point out that the mechanism of neuroprotective agents is clear, and attention to reasonable and standardized application is the key.
However, some experts believe that although neuroprotective agents have a clear mechanism of action, they can save ischemia.
Penumbra has brain cells, but most neuroprotective agents have limited evidence, and their efficacy has not been confirmed by clinical trials
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Over the years, the medical field has been controversial about the treatment of ischemic stroke with neuroprotective agents
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 Therefore, in the "Hundred Debate" Big Coffee Show-Neuroprotectives Symposium hosted by the "Medical Circle", Professor He Zhiyi from the First Affiliated Hospital of China Medical University served as the chair of the conference, Professor Tan Zefeng from the First Affiliated Hospital of Jinan University and Shandong University Professor Zhu Zhengyu from the Second Hospital served as the pros and cons of the seminar, and discussed in detail the "necessity of neuroprotective agents in stroke treatment"
.

Professor He Zhiyi first gave an opening speech.
He said that the incidence of stroke in China ranks first in the world.
There are about 4.
6 million new stroke patients every year, and it is rising at an annual rate of 8.
7%, which brings a heavy burden to individuals and society.

.

The latest data show that about 82% of patients have ischemic stroke.
For acute ischemic stroke, the most basic treatment strategy is vascular recanalization therapy and neuroprotective therapy
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Compared with vascular recanalization therapy, the research progress of neuroprotective agents is slower, and there is still some controversy about its efficacy
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 Professor Zhu Zhengyu: The mechanism of neuroprotective agents is reasonable, but the evidence for most neuroprotective agents is limited.
Professor Zhu Zhengyu holds the opposite view and believes that the treatment of acute ischemic stroke includes the following four aspects: general management, specific treatment, and prevention of complications And treatment, early rehabilitation
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Specific treatments include improving blood circulation in the brain, statins, neuroprotective therapy, traditional Chinese medicine, and other treatment methods.
Specific treatments to improve blood circulation in the brain include recombinant tissue-type plasminogen activator (rt-PA) , urokinase, anticoagulants, vasodilators and so on
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 Vascular recanalization therapy is still the most important treatment for patients with acute ischemic stroke.
In recent years, thrombolysis and thrombectomy therapy have made great progress, but the progress of neuroprotective therapy has been slow
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Although neuroprotective agents do not have strict time window restrictions, they can alleviate brain cell necrosis after cerebral ischemia and save brain cells in the ischemic penumbra by blocking each link of the ischemic cascade.
The relevant mechanism of action is relatively clear.
Theoretically Can bring greater benefits to patients
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However, clinically, there are few products that clearly have neuroprotective effects, and even some products claim to be neuroprotective agents but have no neuroprotective effects, such as gangliosides, cerebrolysin, citicoline, and pirazide that are commonly used in clinical practice.
Tan
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 Professor Zhu Zhengyu pointed out that the research and development of neuroprotective agents has always been a problem all over the world.
In the past, the clinical development of neuroprotective drugs faced a dilemma from basic research to clinical transformation.
Most neuroprotective agents have been proved to have neuroprotective effects in animal experiments, but they are not Clinical trials have had little effect
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In the past 10 years, many promising neuroprotective drugs have been found to reduce infarct size and improve functional scores in the basic research stage, but ultimately ended in clinical trials failing
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 Subsequently, Professor Zhu Zhengyu listed several drugs and the recommendations of the two guidelines: NXY-059 is a free radical scavenger with more therapeutic potential, and its Phase III clinical phase I (SAINT-I) results have achieved significant results.
The results are encouraging, but the primary efficacy endpoint in the SAINT-II trial is not different from placebo
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In addition, the results of clinical trials of drugs such as albumin, uric acid, magnesium sulfate and natalizumab in acute ischemic stroke all ended in failure
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Therefore, more neuroprotective agents with clear curative effects are needed to prove the neuroprotective effect
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In terms of clinical guidelines, neuroprotective agents have not been strongly recommended by the guidelines
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The 2019 U.
S.
Early Treatment Guidelines for Acute Ischemic Stroke pointed out that at present, it is not recommended to use drugs or non-drug treatments that are presumed to have neuroprotective effects
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The 2018 China Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke also proposed that more high-quality studies are needed to further confirm the efficacy and safety of neuroprotective agents
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 The relevant mechanism of action of neuroprotective agents is relatively clear, and theoretically can bring greater benefits to patients
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But so far, most of the neuroprotective drugs have got negative results in the clinical stage, facing the dilemma from basic research to clinical transformation, which has brought a huge blow to the research and development of neuroprotective drugs, and reminded everyone that they cannot be clinically Use neuroprotective agents at will, especially drugs that have negative clinical trials
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Professor Tan Zefeng: Neuroprotective agents have a broader application space.
There are products with clear mechanisms and good results in clinical trials.
Professor Tan Zefeng holds that the current main treatment for acute ischemic stroke is indeed vascular recanalization.
With the improvement of medical standards, the recanalization rate is getting higher and higher, but vascular recanalization treatment has strict time windows, contraindications and time and space limitations.
Many stroke patients cannot receive vascular recanalization treatment.
Relatively speaking, acute ischemia Early application of neuroprotective agents in patients with stroke has broader space
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 There are many types of neuroprotective agents, such as calcium channel blockers, glutamate receptor antagonists, γ-aminobutyric acid (GABA) receptor agonists, free radical scavengers, cell membrane stabilizers, mitochondrial protective agents, anti- inflammatory drugs
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In the past, multiple neuroprotective drugs had negative results in the clinical stage, which brought a huge blow to the research and development of neuroprotective drugs and restricted the clinical application of neuroprotective agents
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Professor Tan Zefeng said that there are many reasons for the failure of previous preclinical research to transform into clinical practice: it may be that the brain structures and functions of humans and experimental animals are different, or it may be that the drug time window in animal experiments is short and the drug dose is large, while in clinical research The optimal drug time window is not clear
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 In view of the current situation that the neuroprotective treatment strategy of ischemic stroke has not made breakthrough progress, Dr.
Marc Fisher and others established the Stroke Treatment Academic Industry Roundtable (STAIR) in the United States.
At the meeting, relevant experts proposed the preclinical ischemic stroke.
Research recommendations
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Under the guidance of the STAIR principle, many new breakthroughs have been made in the research and development of neuroprotective agents, breaking the deadlock of neuroprotective research
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Subsequently, Professor Tan Zefeng described two major studies as arguments: In the ESCAPE-NA1 study, patients with ischemic stroke were randomized to receive a single dose of intravenous Nerinetide (NA-1) or placebo during endovascular treatment
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Although the results of the analysis for all study populations showed that the primary and secondary endpoints of the experimental group and the control group were not significantly different
.

However, in its subgroup analysis, the proportion of patients in the NA-1 group who did not receive rt-PA treatment with a good functional prognosis reached 59.
3%, which was significantly higher than that of the control group (49.
8%)
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This suggests that the application of NA-1 when directly removing the thrombus may bring a better prognosis for the patient
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Figure 1.
The ratio of the experimental group and the control group with good functional prognosis after 90 days [Modified Rankin Scale (mRS): 0-2] is for the ischemic cascade.
Although a single target therapeutic drug successfully inhibits a specific target, But the overall treatment effect is not ideal
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Therefore, it is necessary to shift the research focus to pleiotropic, multi-target neuroprotective drugs, which can intervene in multiple stages of the ischemic cascade to provide neuroprotection
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 Professor Tan Zefeng went on to give an example of a multi-target neuroprotective agent-edaravone dexcamphanol.
The anion of edaravone combines with free radicals to achieve the purpose of scavenging free radicals and protecting cell structure.
Dextrose can inhibit deficiency.
The expression of pro-inflammatory mediators and other inflammation-related proteins caused by blood reperfusion injury can effectively block the cascade of neuronal damage caused by cerebral ischemia and prevent the cascade of pathological changes
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The results of its phase III clinical study (TASTE study) showed that compared with edaravone, edaravone and dexcamphane significantly increased the proportion of patients with acute ischemic stroke that were functionally independent on the 90th day with an odds ratio (OR) of 1.
42.

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The results of the study were also published in the journal STROKE.
At present, edaravone dexcamphanol has been listed in China
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Figure 2.
The mRS scores of the edaravone and edaravone groups on the 90th day.
The research and development of neuroprotective agents has also been in progress.
It is believed that there will be more and more neuroprotective agents with definite therapeutic effects in the future
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After cerebral ischemia occurs, a series of ischemic cascade reactions are produced, and each reaction has a synergistic effect.
Therefore, it may be beneficial to combine neuroprotective agents with different mechanisms of action or to study multiple mechanisms of action in the acute phase of stroke.
This may be a reasonable research idea.
, It is expected to become the research direction of neuroprotection in the future, and we look forward to exploring in the future with a larger sample size
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 The conference concluded and the discussion came to an end.
Professor He Zhiyi first thanked the two professors for their wonderful discussion and sharing of views, and made a summary speech
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Professor Zhiyi He said that vascular recanalization is a key treatment measure for patients with acute ischemic stroke.
Although many neuroprotective agents have had negative results in the clinical stage in the past, we still cannot give up research on neuroprotective agents
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The mechanism of neuroprotection is clear, and it is necessary to rationally use neuroprotective agents with clear curative effects.
The positive results of edaravone and dextrocampine in the phase III clinical trial have strengthened the confidence to continue to develop neuroprotective agents in the future.
The application of neuroprotective agents lays a solid foundation
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This conference is full of dry goods, intense debates and strong learning atmosphere.
I believe that every participant will return with a rewarding experience
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I look forward to more seminars in the future, so that experts can brainstorm ideas and spark ideas
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References: [1]Wang W,Jiang B,Sun H,et al.
Prevalence, incidence, and mortality of strokein China: results from a nationwide population-based survey of 480 687 adults[J].
Circulation, 2017, 135( 8):759-771.
[2]Wang Longde, Liu Jianmin, Yang Yi, et al.
China's stroke prevention and treatment still face huge challenges——Summary of "China Stroke Prevention and Treatment Report 2018"[J].
Circuitry.
2019;34: 105-119.
[3] China Stroke Medical Quality Assessment (QUEST) Collaborative Group.
Current status of acute ischemic stroke treatment in China[J].
Chinese Journal of Neurology.
2009;42(4):223-228.
Expert profile Zhiyi He is currently the director, chief physician, professor, doctoral supervisor of the Department of Neurology of the First Affiliated Hospital of China Medical University, the director of the Liaoning Provincial Neurological Disease Big Data Key Laboratory, and the director of the Liaoning Neurology Quality Control Center.
He was awarded the second "Liaoning Famous Doctor" "Title
.

Served as the Vice President of the Neurology Branch of the Chinese Medical Doctor Association, the Standing Committee Member of the Neurology Branch of the Chinese Medical Association, the Standing Director of the Chinese Stroke Society, the Head of the Neurobiochemistry Group of the Neurology Branch of the Chinese Medical Association, the Standing Director of the Chinese Anti-Epilepsy Association, and the Liaoning Anti-Epilepsy Association Chairman, Chairman of Liaoning Stroke Society, Chairman of the Three Northeast Neurology Exchange Society, and former Chairman of the Neurology Branch of the Liaoning Medical Association
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Served as a member of the editorial board of "Chinese Journal of Neurology" and other magazines
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Dr.
Zhu Zhengyu, the current deputy director of the Second Department of Neurology, Second Hospital of Shandong University, concurrently a member of the First Youth Council of the Chinese Stroke Society, deputy director of the Third Shandong Provincial Medical Association Cerebrovascular Disease Branch, and Shandong Preventive Medicine Association Stroke Vice Chairman of Youth Committee of Prevention and Control Branch, Council Member of Shandong Stroke Association, Member of Cerebrovascular Disease Branch of Shandong Medical Association, Member of Standing Committee of Cerebrovascular Disease Professional Committee of Shandong Association of Gerontology
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The main research directions are cerebrovascular diseases, headaches, and autoimmune diseases of the nervous system
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Participated in and undertook more than 10 provincial and departmental scientific research projects, including the National 973 project, the National Natural Science Foundation of China, the Shandong Natural Science Foundation, the Shandong Science and Technology Development Plan, the Shandong Health Department, and the Shandong Science and Technology Department
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So far, he has published more than 30 papers in domestic and foreign journals, more than 7 papers have been collected by SCI, and he has participated in the editing of 2 monographs
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Won one second prize of Shandong Provincial Science and Technology Progress Award, and one third prize of Shandong Provincial Department of Education for Outstanding Scientific Research Achievement Award of Colleges and Universities
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Tan Zefeng is a doctor of clinical medicine, an associate chief physician, a postgraduate tutor, and the administrative deputy director of the Department of Neurology of the First Affiliated Hospital of Jinan University
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Vice Chairman of the Youth Council of the Chinese Stroke Society, Deputy Head of the Neuroimaging Group of the Neurology Branch of the Guangdong Medical Association, Youth Member of the Cerebrovascular Diseases Branch of the Guangdong Medical Association, Member of the First Clinical Research Branch of the Guangdong Medical Association, Member of the First Cerebral Vascular Disease Branch of the Guangdong Medical Doctor Association, member of the Standing Committee of the First Cerebral Blood Flow and Metabolism Branch of the Guangdong Stroke Society, Secretary of the Acute Cerebrovascular Disease Emergency Network in Tianhe District, Guangzhou, Stroke and Vascular Neurology Journal (Impact Factor 4.
75) Responsible sub-editor and reviewer
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