2022 annual inventory: from "neuroprotection" to "brain cell protection", stroke treatment concept is more comprehensive

*For medical professionals only

How progress has been made in brain cell protectors in 2022, these highlights should not be missed!

At present, stroke has become the second leading cause of death in the world, and it is also the first fatal and disabling disease in adults in China, of which acute ischemic stroke (AIS) is the most important type
of stroke.
At present, intravenous thrombolysis and endovascular mechanical thrombectomy are effective vascular recanalization measures recommended by domestic and foreign guidelines, and opening occluded blood vessels as soon as possible is the key to AIS treatment, but the clinical prognosis of patients is not ideal, and patients still have unmet treatment needs ^[1].

Neuroprotection is another important means of treating AIS, but despite the encouraging results of various neuroprotective agents in preclinical trials in the past, none of them have achieved the desired results
after entering phase III clinical trials.
This also reflects the shortcomings of previous neuroprotective therapies ^[2].

In 2022, many breakthroughs have been made in stroke treatment, among which more and more experts and scholars realize that the concept of "neuroprotection" may not be appropriate in the past, and the concept of "brain cell protection" has emerged, becoming one of
the hottest topics in stroke treatment at home and abroad.

From "neuroprotection" to "brain cell protection", the understanding of stroke mechanism is more comprehensive

The mechanism of ischemic stroke is extremely complex, and neuroprotective drugs act on neurons, and their main pharmacological effects are to inhibit intracellular calcium transfer, neurotransmitter release and neuronal apoptosis ^[3].

。 With the continuous improvement of medical level, medical researchers realized that neurons, glial cells, vascular endothelial cells, etc.
after cerebral ischemia are damaged to varying degrees after ischemic stroke, and with the concept of neurovascular unit, the treatment of stroke has changed from a single neuron protection to the protection of all components of the neurovascular unit ^[4].

The concept of brain cell protection therapy breaks through the previous definition of "saving ischemic tissue that is still likely not to continue to progress to infarction foci", and the scope is not limited to the narrow sense of "protecting neurons", but refers to the overall protection of the structure of the "neurovascular unit", while taking into account astrocytes, microglia and the brain support structures around neurons
.
Expanding the goal of neuroprotection to comprehensive protection of all components of the neurovascular unit, and drug protection targets also targeting various targets of the neurovascular unit after cerebral infarction, may be more effective in the treatment of ischemic brain injury ^[3,4].

Figure 1: Composition of the neurovascular unit

The multi-target brain cell protector "report card" is here, and 2022 is full of highlights

Given the complex pathophysiological process of ischemic stroke, involving excitotoxicity, oxidative stress, inflammatory mechanisms, etc.
, the ideal brain cell protection drug should act on multiple targets
at the same time.
Edaravone dexturol injection is the only approved multi-target brain cell protector, as a composite preparation, edaravone dextrol can scavenge oxygen free radicals, inhibit oxidative stress damage and inflammatory response after ischemia/reperfusion, thereby achieving the role of protecting brain cells, and has demonstrated clear clinical benefits
in related clinical studies.

What important progress has been made with edaravone dextronicol in 2022? Let's take a look together:

▌ The TASTE-II study completed the first patient medication to evaluate the effect of edaravone dextrol combined with early endovascular recanalization

The TASTE-II study is a multicenter, randomized, double-blind, placebo parallel controlled clinical trial
led by Professor Wang Yongjun, Chairman of the Neurology Branch of the Chinese Medical Association and President of Beijing Tiantan Hospital.
The study plans to enroll more than 1,300 AIS patients with onset within 24 hours and receiving early endovascular recanalization therapy (bridging therapy or direct endovascular therapy) in more than 100 research centers across the country to evaluate the efficacy and safety of edaravone dextrol in AIS patients receiving early endovascular recanalization ^{therapy [5].}

In March 2022, the first patient was dosed in Beijing Tiantan Hospital affiliated to Capital Medical University
.

▌Edaravone dextrol was written into the "Guidelines for the Construction of Stroke Prevention and Treatment System"

At the beginning of 2022, the first monograph of the "323" Attack Action Series in Hubei Province "Guidelines for the Construction of Stroke Prevention and Control System" was released
.
Among them, edaravone dextrol was included in the "Neuroprotective Treatment and Recommendations" chapter of the book with high-quality clinical research data
.

In the chapter on neuroprotective therapy, the work recommends: "Edaravone dextronicol can significantly improve the functional outcomes of ischemic stroke patients through free radical scavenging, anti-inflammatory, anti-glutamate excitatory toxicity, mitochondrial protection and other multi-target blockade of cerebral ischemic cascade, and is safe for clinical use, providing a new and more effective clinical treatment for
the treatment of acute ischemic stroke.
" ”^[6]

▌A new application of edaravone dextronicol: Exploration of neuroprotective therapy for subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke that accounts for about 10% of acute strokes and has a high rate of disability and fatality
.
Currently, there is a lack of satisfactory neuroprotective drugs
for secondary brain injury for SAH.

A basic study published in April by the team of Professor Sun Baoliang of the Second Affiliated Hospital of Shandong First Medical University explored the therapeutic effect
of edaravone dextrol on SAH-induced brain injury and long-term neurological deficits.
The results showed that edaravone dextronicol helped improve neurological function for up to 21 days after SAH surgery in mice, which was more beneficial than edaravone alone^[7].

This study suggests that edaravone dextrol may become a neuroprotective drug
for the treatment of post-SAH brain injury.
It is expected that more clinical studies will help the expansion of edaravone dexturol in the field of SAH in the future
.

Figure 2: Edaravone treatment improves sensorimotor function after SAH

▌The clinical evidence of edaravone dextrol appeared at the 8th European Stroke Congress and attracted much attention

In May 2022, a study led by the team of Qu Lixin, director of Dezhou People's Hospital in Shandong Province, was presented at the 8th European Stroke Congress (ESOC), which compared the efficacy and inflammation-related factors of four different treatment regimens: edaravone dextrol monotherapy, thrombolytic therapy monotherapy, conventional treatment, and edaravone dextrol combined with thrombolytic therapy on neurological recovery and inflammation-related factors in AIS patients [^8].

。

The results showed that edaravone dextrol significantly reduced the level of inflammatory factors and improved neurological function in AIS patients regardless of whether they received thrombolytic therapy, among which the combination of edaravone dextrol and thrombolytic drugs was the most obvious
improvement.

Table 1: Comparison of changes in various indicators before and after treatment

▌Basic studies have shown that the mechanism of edaravone dextrol in reducing cerebral ischemic injury is related to the upregulation of MKP-1 expression

Professor Du Guanhua's team of Peking Union Medical College Hospital used a rat model of four-vessel occlusion (4-VO) to observe the efficacy of edaravone dextrol and explore the specific mechanism of action, and the results were officially published in BioMed Research International in September 22 ^[9].

The results showed that edaravone dextronicol inhibited phosphorylation of MAPKs, inhibited the activation of NF-κB p65, and promoted the expression of Nrf2 by upregulating MKP-1, and the interaction of MKP-1 and Nrf2 enhanced the antioxidant capacity of cells and had a protective effect against cerebral ischemic damage.
At the same time, edaravone combined with dextrostanol is better than edaravone
alone.
This study preliminarily suggests that MKP-1 may be a protein necessary for edaravone dextrol to activate the Nrf2 signaling pathway, and up-regulation of MKP-1 activity provides a promising strategy
for stroke treatment.

Figure 3: Edaravone dexturinol has an upregulation effect on MKP-1 in 4-VO rat brain tissue, and the MKP-1 inhibitor BCI can counteract the overexpression of edaravone dexturine alcohol-induced MKP-1

▌Pharmacoeconomic research data of edaravone dextrol was released, and the cost-effect advantage was clear

In October, the team of Professor Han Sheng of Peking University School of Pharmacy evaluated the cost-efficacy of edaravone dextrol in the treatment of stroke based on the evidence of clinical benefit of TASTE study and the current situation of social and economic development in China ^[10].

The results showed that edaravone dextronicol was a cost-effect advantage compared with edaravone treatment.
The results of univariate sensitivity analysis and probabilistic sensitivity analysis also confirmed the robustness and consistency of the basic analysis results, among which the probability of edaravone dextrol having pharmacoeconomic advantages over edaravone in 1-year, 5-year and 30-year simulations was 76.
3%, 98.
9% and 99.
5%, respectively
.

Table 2.
Cost-effect analysis results of edaravone dexturine vs edaravone under different simulation time limits

▌ Edaravone dextronicol sublingual tablet form achieved satisfactory preliminary results

Edaravone Dextrol Sublingual Tablets is an oral solid preparation, each tablet contains edaravone 30mg, dextherol 6mg, these two active ingredients can rapidly disintegrate under the tongue, absorbed through the sublingual venous plexus, enter the center to exert anti-inflammatory, anti-free radical and protect the blood-brain barrier, thereby reducing brain cell damage
caused by stroke.

The phase III clinical study of edaravone dextrogenol sublingual tablets was led by Peking University Third Hospital, and more than 900 patients with AIS with an onset time of ≤ 48 hours were included in nearly 40 research centers across the country, aiming to evaluate the efficacy and safety
of edaravone dextrogenol sublingual tablets in the treatment of AIS patients.

Recently, the study has completed database locking (DBL).

Preliminary analysis showed that compared with placebo, edaravone dextronicol sublingual tablets significantly improved the recovery of neurological function and independent living ability of AIS patients after treatment, and achieved the expected efficacy endpoint, with good safety ^[11].

This study confirmed the clinical value of edaravone dextronicol tablets in the treatment of AIS, and is expected to bring new treatment options
to the majority of AIS patients.

small

knot

Ischemic stroke is one of the important diseases that threaten human health, and its occurrence and development can trigger a series of complex pathophysiological changes, including oxidative stress and inflammatory mechanisms
.
With a comprehensive understanding of the mechanism of stroke, academia has abandoned the concept of "neuroprotection" and began to move to a more comprehensive concept
of "brain cell protection".
Edaravone dextrol is a multi-target brain cell protector, which has made important research progress in 2022 and is fruitful, and it is expected that it will bring more benefits to stroke patients in the future!

References:

JIA Milan, ZHAO Wenbo, LI Sijie, et al.
Research progress in prevascular recanalization of acute ischemic stroke[J].
Chinese Journal of Cerebrovascular Diseases.
2022; 19(8): 576-581.

[2] Xiao Weimin, Cheng Weiyang.
Current status and research prospect of neuroprotective agents for ischemic stroke[J].
Internal Medicine Theory and Practice.
2019; 14(5): 282-288.

[3] YANG Guoyuan, HE Xiaosong, WANG Yongting.
The role and significance of neurovascular unit in the treatment of cerebral ischemia[J].
Chinese Journal of Modern Neurological Diseases.
2011; 11(2): 125-131.

LIANG Ping, MENG Lanqing, HUANG Qing, et al.
Research progress on molecular targets of neurovascular units in ischemic stroke[J].
Journal of Youjiang Medical College for Nationalities.
2019; 41(5): 568-571.

[5] Treatment of Acute Ischemic STroke With Edaravone Dexborneol II (TASTE-2).
https://clinicaltrials.
gov/ct2/show/NCT05249920.

[6] World Stroke Prevention Day | must be newly written into the "Guidelines for the Construction of Stroke Prevention and Control System" https://mp.
weixin.
qq.
com/s/qFc5X0psFTQTFgW8x5etHg

[7] Chen Q, Cai Y, Zhu X, Wang J, et al.
Edaravone Dexborneol Treatment Attenuates Neuronal Apoptosis and Improves Neurological Function by Suppressing 4-HNE-Associated Oxidative Stress After Subarachnoid Hemorrhage[J].
Front Pharmacol.
2022 Apr 21; 13:848529.

[8] Effects of Edaravone Dexborneol on Neurological Function and Serum Inflammatory Factors in Patients with Acute Ischemic Stroke.
ESOC 2022, P0009.

[9] Zhang W, Yang H, Gao M, et al.
Edaravone Dexborneol Alleviates Cerebral Ischemic Injury via MKP-1-Mediated Inhibition of MAPKs and Activation of Nrf2[J].
Biomed Res Int.
2022 Sep 6; 2022:4013707.

[10] Shi F, He Z, Wang L, et al.
Cost-effectiveness of edaravone dexborneol versus edaravone for the treatment of acute ischemic stroke in China: based on the TASTE study[J].
Frontiers in Pharmacology, 2022, 13: 938239.

[11] Positive results! The phase III clinical trial of sublingual tablets in the treatment of acute ischemic stroke reached the expected efficacy endpoint https://mp.
weixin.
qq.
com/s/nlMROdYZb7DEDwlq14Igaw

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