From June 14 to 16, 2024, the 10th Annual Conference of the Chinese Stroke Society and the Tiantan Cerebrovascular Disease Conference 2024 (CSA&TISC 2024) was held in Beijing. In the sub-session of "Secondary Prevention of Stroke - Risk Factors", Professor Zhao Xingquan from Beijing Tiantan Hospital Affiliated to Capital Medical University gave an academic report entitled "Research on Multi-target Brain Protection in Ischemic Stroke".
Ischemic stroke is the main type of cerebrovascular disease in mainland China and the leading cause of disability. The treatment goal of acute ischemic stroke (AIS) is to salvage the nerve cells around the infarct that have malfunctioned due to ischemic injury but have not yet died, and to promote the recovery of neurological function, that is, to rescue the "ischemic penumbra".
- The pathophysiological processes of ischemic stroke include cell excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier damage, and cell death.
- Targeted modulation of pathways can be used as a potential therapeutic strategy.
- A brain protectant is any drug that can reduce ischemic brain injury events by antagonizing harmful molecules rather than improving blood flow to the brain. Targeting the key mechanism of ischemic penumbra injury, the brain protector covering multiple nerve injury mechanisms may block the cerebral ischemia cascade, resist nerve injury, prolong the treatment time window, help reduce brain tissue damage caused by reperfusion, and reduce sequelae.
Clinical study of brain protectants
Previous studies of single-target cerebral protective agents have mostly yielded negative results. The results of ESCAPE-NA1, TASTE, BAST and other studies suggest that brain protective agents with multi-target protective effects may improve the functional outcomes of ischemic stroke patients.
- ESCAPE-NA1: Among patients who did not receive intravenous thrombolysis, the proportion of patients who recovered from NA-1 therapy was significantly increased compared with placebo;
- TASTE: Edaravone dexprenol can effectively improve functional outcomes in patients with ischemic stroke;
- BAST: butylphthalide plus reperfusion therapy may improve the proportion of good functional outcomes at 90 days post-stroke.
In August 2023, a randomized, double-blind, placebo parallel-controlled, multicenter clinical study of the efficacy and safety of ginkgo diterpene lactone meglumine injection in the treatment of AIS was published in JAMA Network Open (IF=13.800).
The study focused on AIS patients with no obvious sequelae (mRS≤1 before the onset of this disease), NIHSS score of 4~24 points, and limb motor sub-score ≥of 2 points within 48 hours of onset, the first onset or previous stroke, and a total of 3448 subjects recruited from 100 research centers in China, of which 1725 received ginkgo diterpene lactone meglumine injection and 1723 received placebo.
Inclusion Criteria:
- Age 18~80 years old, male or female;
- Ischemic stroke within 48 hours of onset (the diagnostic criteria were based on the criteria of the Fourth National Conference on Cerebrovascular Diseases of the Chinese Medical Association);
- First onset, or no significant sequelae of previous stroke (mRS≤1 before this episode);
- The degree of neurological deficit score (NIHSS) is 4~24 points, and the limb motor subscore (total score of items 5 and 6 of the NIHSS score) is ≥ 2 points;
- Informed consent voluntarily signed by the patient or his/her legal representative and approved by the Ethics Committee was obtained.
The results showed that: (1) For AIS patients treated with ginkgo diterpene lactone meglumine injection within 48 hours of onset, compared with the placebo group, the patients in the ginkgo diterpene lactone meglumine injection group had better 90-day good functional outcomes (Table 1, Figure 1); (2) The results of subgroup analysis showed that the therapeutic effect of ginkgo diterpene lactone meglumine injection was consistent among different characteristic populations.
Table 1 Main efficacy measures
Fig.1 Distribution of mRS scores
Note: GDLM is ginkgo diterpene lactone meglumine injection
Conclusions: (1) For AIS patients treated within 48 hours of onset, ginkgo diterpene lactone meglumine injection can increase the proportion of mRS 0~1 points after 90 days and improve the functional prognosis of patients; (2) Studies suggest that multi-target brain protective agents can be used for the treatment of AIS and improve the functional prognosis of patients.
Exploratory study - cognitive function outcomes
According to statistics, 2~6 months after stroke, 44% of people are impaired in overall cognition, and 30%~35% are impaired in a single domain; The cognitive decline rate of stroke patients was faster than that of the non-stroke control group 1~3 years after the onset of the disease, and the score difference was 0.078 SD/year.
In order to study the effect of ginkgo diterpene lactone meglumine injection on the cognitive function of AIS patients, a secondary analysis was conducted on the clinical trial of ginkgo biloba diterpene lactone meglumine injection for the treatment of AIS, and the main outcome was the change of Montreal Cognitive Assessment Scale (MoCA) score from baseline to day 14 and day 90 after randomization. Finally, 3163 AIS subjects were included in the study, including 1588 in the ginkgo diterpene lactone meglumine injection group and 1575 in the placebo control group.
Secondary analysis
Key outcomes:
- Change in MoCA score from baseline to day 14 and day 90 after randomization;
Secondary outcomes:
- Proportion of patients with clinically significant improvement in MoCA from baseline to day 14 and day 90 after randomization (an improvement of at least 2 points in MoCA score is considered clinically significant);
- Changes in the subcomposition of MoCA.
The results were as follows: (1) Compared with the control group, the MoCA score of the Ginkgo diterpene lactone meglumine injection group increased by 0.31 points after 14 days of randomization and 0.47 points after 90 days (Table 2) ;(2) Compared with the control group, the patients with clinically significant MoCA score increased by 25% and 21%, respectively, compared with the control group; (3) In terms of visual space and executive ability, language, and abstraction, Ginkgo biloba diterpene lactone meglumine injection group had significant improvements (Table 3).
Table 2 MoCA score changes from baseline to 14 and 90 days after randomization
Table 3 Changes in MoCA subcomponent scores from baseline to 14 and 90 days after randomization
Conclusions: (1) Compared with placebo, ginkgo diterpene lactone meglumine injection treatment could significantly improve cognitive function at day 14 and day 90 in AIS patients treated within 48 hours of onset; (2) The results of this study still need to be validated in larger studies.
Mechanism exploration
Ginkgo diterpene lactone meglumine injection contains the therapeutic active ingredients ginkgolide A, B and K, which are specific platelet-activating factor (PAF) receptor antagonists, which can treat ischemic stroke through multiple targets and multiple pathways: (1) ginkgo diterpene lactones antagonize PAF receptors and inhibit platelet aggregation; (2) Ginkgo diterpene lactones inhibit PAF-induced inflammatory response; (3) Ginkgolide K alleviates endoplasmic reticulum stress; (4) Ginkgo diterpene lactones resist oxidative stress and inhibit apoptosis.
Ginkgo diterpene lactone meglumine injection has a multi-pathway effect with PAF receptor as the main target, which provides a new approach and basis for the short-term and long-term treatment of ischemic stroke. The recently released "Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke in China 2023" pointed out that a number of domestic and foreign RCT studies based on neuroprotection recommend the individualized application of brain protective agents such as ginkgo diterpene lactone meglumine (level II. recommendation, level B evidence).
Summary
1. The treatment goal of acute ischemic stroke is to "light" the ischemic penumbra, and brain protective agents can effectively intervene against the targets of the mechanism of nerve injury.
2. More emphasis is placed on the protection of the "neurovascular unit" structure as a whole, and cerebral protective agents with multi-target protective effects may improve the functional outcomes of ischemic stroke patients.
3. For patients with AIS who had onset for 48 hours, ginkgo diterpene lactone meglumine treatment could effectively improve the proportion of patients with good functional prognosis at 90 days.
4. Ginkgo biloba diterpene lactone meglumine treatment can also effectively improve the cognitive function of AIS patients at 14 days and 90 days.
5. PAF-PAFR antagonists have multiple effects such as antiplatelet, anti-inflammatory, and inhibition of apoptosis, and have significant advantages in the comprehensive treatment of stroke.
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