Role of salvianolic acid B in the treatment of acute ischemic stroke: a systematic review and meta-analysis of animal models

Abstract

Background:

Salvianolic acid B (Sal B) is potentially the most valuable water-soluble active component in Salvia miltiorrhiza. Its chemical formula contains multiple phenolic hydroxyl groups, so it has a strong antioxidant capacity.

Objective:

We aim to investigate the efficacy and the potential mechanism of Sal B in the treatment of acute ischemic stroke injury.

Materials and methods:

CNKI, VIP, WanFang, SinoMed, PubMed and Web of Science were searched for all the literature related to Sal B in the treatment of acute ischemic stroke before August 2024. The methodological quality was assessed using an inspection scale combining the CAMARADES checklist and the new STAIR criteria. Data were analyzed using RevMan5.4 software.

Results:

A total of 14 articles were included. Sal B could effectively reduce infarct size, neurological deficit score, brain edema index, and brain water content in cerebral ischemic animals. Sal B could not only increase the content of superoxide dismutase (SOD) and decrease the content of malondialdehyde (MDA) to achieve anti-oxidative stress, but also reduce the level of interleukin-1β (IL-1β) protein to achieve anti-inflammatory response, and reduce the number of TUNEL cells to reflect its anti-apoptosis effect. In addition, Sal B can improve energy metabolism by increasing the content of energy charge (EC) and phosphocreatine (PCr), and maintaining ion balance via Na⁺/K⁺ ATPase activity, resulting in the neuroprotective effects against acute ischemic stroke injury.

Conclusion:

This study showed that Sal B could significantly protect against acute ischemic stroke injury, mainly through anti-oxidative stress, anti-inflammatory response, anti-apoptosis, improving energy metabolism, and stabilizing ion balance.

1 Introduction

Salvia miltiorrhiza is the dried root and rhizome of Salvia miltiorrhiza in the Labiatae family, which has the effects of vasodilation, myocardial protection, anti-atherosclerosis and anti-thrombosis (Giugliano et al., 2020; Wang G. et al., 2022; He and Chen, 2020; Rosińska et al., 2017), and is widely used in clinical treatment of various cardiovascular and cerebrovascular diseases, including coronary heart disease, myocardial infarction and stroke caused by cerebral ischemia, dementia (Fang et al., 2018; Qin et al., 2021; Guo and Wang, 2022). Chinese Pharmacopoeia (2020 edition) stipulated that the total amount of tanshinone-containing tanshinone I, IIA and cryptotanshinone should not be less than 0.25%, and salvianolic acid B (Sal B) should not be less than 3.0% as the quality evaluation standard of salvianolic acid. Sal B is a water-soluble compound, while tanshinone I, tanshinone IIA and cryptotanshinone are lipid-soluble compounds (Chinese Pharmacopoeia Commission, 2020). Therefore, Sal B is potentially the most valuable water-soluble active component in Salvia miltiorrhiza.

Sal B is a monomer compound formed by the condensation of three molecules of 3,4-dihydroxyphenyllactic acid and one molecule of caffeic acid (Figure 1) (He et al., 2023). There are several phenolic hydroxyl groups in the molecular structure of Sal B, indicating strong antioxidant activity property (Loaiza-Cano et al., 2020). Recently, research results show that Sal B possesses various pharmacological characteristics, such as anti-inflammatory and anti-apoptotic effects contributing to improve the injury of acute ischemic stroke (Lee et al., 2023; Xiao et al., 2020; Zheng et al., 2021). Sal B has minor side effects with a higher margin of safety (Ding et al., 2017).

FIGURE 1

Several studies have reported the neuroprotective effects of Sal B on acute ischemic stroke injury (Zhu et al., 2022). The mechanisms underlying its neuroprotective effects have been investigated in animal models of acute ischemic stroke in recent years. In this study, we conducted a systematical review and meta-analysis of studies in animals, aiming at evaluating the therapeutic effects of Sal B against acute ischemic stroke and determining the relevant mechanisms of Sal B in the treatment of acute ischemic stroke, hopefully providing scientific evidence for the clinical application of Sal B in protecting against acute ischemic stroke injury.

2 Materials and methods

This study was reported in accordance with the PRISMA principles (Moher et al., 2009) and the Cochrane Collaboration guidance (Cumpston et al., 2019).

2.1 Literature retrieval strategy

In this study, the Chinese Medical Subject Headings (MeSH) of the National Library of Medicine was used to determine the item term of “ischemic stroke” (DeMars and Perruso, 2022), and the following search strategies were established according to the results: (Sal B) AND (ischemic stroke OR cerebral ischemia OR cerebrovascular disease OR cerebral infarction OR cerebral infarction OR cerebral embolism). Six databases including CNKI, VIP, WanFang, SinoMed, PubMed and Web of Science were searched by two researchers independently. The search period was up to August 2024, and the language of the publications was not restricted. The search results were imported into reference management software.

2.2 Study inclusion and exclusion criteria

Experimental studies in animal models of acute ischemic stroke were included, with no restrictions on animal species, strain, sex, or modeling methods. The experimental group was the acute ischemic stroke model injected with Sal B, and the control group was the acute ischemic stroke model without Sal B injection.

Exclusion criteria were as follows: (1) Duplicate or irrelevant literature; (2) Reviews, conference proceedings, dissertations, informal journals, catalogs, etc.; (3) Clinical and other in vitro studies; (4) Animal models unrelated to acute ischemic stroke; (5) Studies involving combination therapies; (6) Studies with incomplete or missing data; (7) Outcome measures could not be extracted or combined.

2.3 Outcome measures

All indicators were divided into primary indicators and secondary indicators according to whether they could directly reflect the efficacy (Li and Zhang, 2021; Zhang et al., 2005). Primary outcome measures included infarct size, neurological deficit score, and brain edema index (brain index, brain water content). Secondary indicators included oxidative stress markers (SOD, MDA), inflammatory markers (IL-1β protein level), apoptosis index (number of TUNEL-positive cells), and cytotoxic edema markers (EC, PCr, Na⁺/K⁺ ATPase activity, lactate).

2.4 Literature screening and data extraction

Two researchers searched independently according to strict inclusion and exclusion criteria, and all data were screened and extracted in Noteexpress software. Any disagreements on the eligibility of studies were resolved by discussing with the third investigator.

Data were extracted from original text, tables, figures, supplementary materials and methods, and references. GetData Graph Digitizer software was used to extract data in literature that only presented data in the form of images. The experimental part included intervention design, administration route, administration dose, treatment time, and outcome indicators, in which the outcome indicator was the difference of Sal B before and after intervention. The model part included animal species, strain, sex, age, weight, ischemia type and modeling method. The material section included drug purity, source, etc. In addition, general information such as author, country, and year of publication was collected.

2.5 Quality assessment and risk of bias

An inspection scale (Aliena-Valero et al., 2021) including the CAMARADES (Sena et al., 2007) criteria and the STAIR criteria (Fisher et al., 2009) was used for quality assessment: (1) Published in a peer-reviewed journal; (2) Temperature control declaration; (3) Randomization; (4) Hidden allocation; (5) Blinded evaluation; (6) Use of anesthetics without neuroprotective properties (e.g., chloral hydrate); (7) In addition to ischemia, the experimental animals had complications; (8) Clarifying the sample size; (9) Comply with animal welfare regulations; (10) Reported potential conflicts of interest; (11) Timely detection of animal physiological indicators; (12) Clear inclusion and exclusion criteria; (13) There were reports of animal culling; (14) Funding report (15) Modeling success was confirmed by techniques such as laser Doppler or perfusion imaging.

2.6 Statistical analysis

Statistical software Rev man 5.4 was used to analyze the collected data. The mean difference (MD) or standardized mean difference (SMD) was used to report the pooled effect estimate for continuous variables with their 95% confidence interval (CI). Heterogeneity among studies was categorized by the I² statistic as follows: I²<50% indicated low or non-significant heterogeneity, and the fixed effect models were used, and I² > 50%, represented high heterogeneity, and the random effect models were used. For the literature with high heterogeneity, subgroup analysis or sensitivity analysis was further analyzed according to the actual situation to determine the source of heterogeneity.

3 Result

3.1 Included literature

A total of 686 literatures were retrieved from six databases including CNKI and Wanfang. Among these, 359 duplicates and 114 reviews, conferences, dissertations, unofficial journals, and catalog literature were excluded. We screened the literature according to the title and abstract of the literature, and excluded the literature of non-non-animal models (n = 97), non-salvianolic acid B (n = 72), combination drugs (n = 9), and loss of original text and incomplete data reporting (n = 9), leaving 27 literatures were reviewed, and a further 13 excluded. The remaining 14 articles finally met the inclusion criteria and were included in the meta-analysis. The study selection flow chart is shown in Figure 2.

FIGURE 2

3.2 Study characteristics and quality assessment

Tables 1, 2 summarize the characteristics of the included studies. Of the 14 studies, 7 studies were conducted in rats and 7 in mice. The dosage of Sal B ranged from 10 mg/kg to 192 mg/kg, and was administrated via the tail veins or intraperitoneal injections. All studies used anesthetics with no apparent intrinsic neuroprotective properties. Two studies did not explicitly mention the non-randomized controls, and the rest of the studies were randomized controlled trials. In the study design, two studies mentioned the use of a blinded method to assess outcomes, three studies had pre-specified inclusion and exclusion criteria, and one study reported the exclusion of animals for analysis. One study did not mention temperature control during ischemia induction. In addition, nine studies explicitly issued statements of compliance with animal welfare requirements, and eleven studies explicitly reported research funding. The results are shown in Table 3.

3.3 Included literature

3.3.1 Infarct size

Seven studies (Bi et al., 2022; Fan et al., 2018; Wang G. et al., 2019; Wang X. et al., 2019; Xiao et al., 2014; Zhao et al., 2008b; Zheng et al., 2023) reported the effects of Sal B on infarct size following acute ischemic stroke injury. The results showed that Sal B could effectively reduce infarct size (MD = −16.93, 95%CI = [−23.01, −10.85]; I² = 97%, P < 0.0001) (Table 4).

3.3.2 Neurological deficit score

Four studies reported the effects of Sal B on neurological deficit score (Wang G. et al., 2019; Wang H. et al., 2016; Xiao et al., 2014; Zhao et al., 2008a). The results showed that Sal B could effectively reduce neurological deficit score (MD = −0.86, 95% CI = [−1.29, −0.42]; I² = 75% P = 0.001) (Table 4).

3.3.3 Brain index

Five studies reported the effects of Sal B on brain index following acute ischemic stroke injury (Fang et al., 2016; Jiang et al., 2007; Wang G. et al., 2019; Xiao et al., 2014; Zhang et al., 2007). The results showed that Sal B could effectively reduce the brain index (MD = −0.01, 95%CI = [-0.02, −0.00]; I² = 91%; p = 0.02) (Table 4).

3.3.4 Brain water content

Six studies (Fang et al., 2016; Jiang et al., 2007; Wang G. et al., 2019; Xiao et al., 2014; Zhang et al., 2007; Zheng et al., 2023) reported the effects of Sal B on brain water content following acute ischemic stroke injury. The results showed that Sal B could effectively reduce brain water content (MD = −1.87, 95%CI = [−3.50, −0.23]; I² = 99%; P = 0.03) (Table 4).

3.3.5 SOD

Four studies (Chen et al., 2000; Lv et al., 2019; Wang G. et al., 2019; Zhao et al., 2008a) reported the effects of Sal B on brain SOD content following acute ischemic stroke injury. The results showed that Sal B could significantly increase the activity of SOD (MD = 13.06, 95%CI = [−3.26, 22.86]; I² = 98%; P = 0.0009) (Table 4).

3.3.6 MDA

Four studies (Chen et al., 2000; Lv et al., 2019; Wang G. et al., 2019; Zhao et al., 2008a) reported the effects of Sal B on brain MDA content following acute ischemic stroke injury. The results showed that Sal B could significantly increase the activity of MDA (MD = 4.90, 95%CI = [−7.51, 2.29]; I² = 98%; P = 0.0002) (Table 4).

3.3.7 IL-1β protein levels

Two studies reported the effects of Sal B on IL-1β protein levels following cerebral ischemic injury (Fan et al., 2018; Zheng et al., 2023). The results showed that Sal B could effectively increase the content of IL-1β protein (MD = 0.18, 95%CI = [−3.02, −0.03]; I² = 83%; P = 0.02) (Table 4).

3.3.8 The number of TUNEL-positive cells

Three articles [24, 29, 36] reported the effects of Sal B on the number of TUNEL-positive cells in the ischemic brain tissues. The results showed that Sal B could effectively reduce the number of TUNEL-positive cells (MD = −19.64, 95%CI = [−35.81, −3.47]; I² = 97%; P = 0.02) (Table 4).

3.3.9 Energy charge

Two articles (Jiang et al., 2007; Zhang et al., 2007) reported the effects of Sal B on EC. The results showed that Sal B could effectively improve EC (SMD = 0.05, 95%CI = [0.02, 0.08]; I² = 10%; P = 0.0004) (Table 4).

3.3.10 Phosphocreatine

Two articles (Jiang et al., 2007; Zhang et al., 2007) reported the effects of Sal B on brain PCr activity. The results showed that Sal B could effectively improve the PCr content (SMD = 10.49, 95%CI = [4.75, 16.22]; I² = 0%; P = 0.0003) (Table 4).

3.3.11 Na⁺/K⁺ ATPase activity

Two studies reported the effects of Sal B on brain Na⁺/K⁺ ATPase activity (Jiang et al., 2007; Zhang et al., 2007). The results showed that Sal B could effectively improve Na⁺/K⁺ ATPase activity (SMD = 0.59, 95%CI = [0.32, 0.86]; I² = 0%; P < 0.00001) (Table 4).

3.3.12 Lactate

Two articles reported the effects of Sal B on brain lactate content (Chen et al., 2000; Jiang et al., 2007). The results showed that Sal B could effectively reduce brain lactate content (MD = −1.6, 95%CI = [−2.79, −0.40]; I² = 88%; P = 0.009) (Table 4).

3.4 Sensitivity analysis

3.4.1 Infarct size

Subgroup analyses used the duration of treatment as the grouping criterion. We found that the I² decreased to 29% for treatment duration of less than 24 h (P < 0.00001), 53% for treatment duration of 25 h to 7 days (P < 0.00001), and 43% for treatment duration of more than 7 days or more than 24 h or less than 25 h, suggesting that differences in treatment duration may be the main source of heterogeneity. The new pooled results showed that Sal B was effective in reducing infarct size (Figure 3).

FIGURE 3

3.4.2 Neurological deficit score

Subgroup analyses were conducted using the duration of treatment as the grouping criterion (<24 or ≥24 h). The results showed that Sal B could effectively reduce the neurological deficit score (Figure 4).

FIGURE 4

3.4.3 Brain index

Subgroup analysis was conducted based on the timing of administration. The results showed that there was still a significant difference in the pre-ischemia group, and the difference was not statistically significant (I² = 87%, P = 0.20). However, I² decreased significantly to 48% (P = 0.0003) in the post-ischemia group, suggesting that timing of administration may be a potential source of brain index heterogeneity. The results support that Sal B can effectively reduce brain index. See Figure 5.

FIGURE 5

3.4.4 Brain water content

The timing of administration was used as the criterion for subgroup analysis. In subgroup analysis of brain water content, It was observed that I² decreased to 73% (P = 0.007) in the pre-ischemia group, whereas I² remained at 99% after ischemia. Thus, different timing of administration may be the primary source of heterogeneity, and the results support the efficacy of Sal B in reducing brain water content after ischemia. See Figure 6.

FIGURE 6

3.4.5 SOD

Subgroup analysis was conducted based on the timing of administration. Results indicated no statistical significance in administration before acute ischemic stroke (P = 0.30), but I² decreased to 81% after acute ischemic stroke (P = 0.007), which was statistically significant, suggesting that different timing of administration may be the potential source of heterogeneity. Nevertheless, the results support the ability of Sal B to increase SOD content after acute ischemic stroke. See Figure 7.

FIGURE 7

3.4.6 MDA

Subgroup analysis was conducted based on the timing of administration. The results showed that there was no statistical significance in preischemic stroke administration (P = 0.28), but Z was 4.12 (P < 0.00001) after ischemic stroke administration. This finding was statistically significant, suggesting that different timing of administration might be a potential source of heterogeneity. However, the results still support the efficacy of Sal B in reducing MDA content after acute ischemic stroke. See Figure 8.

FIGURE 8

3.4.7 The number of TUNEL-positive cells

After systematically excluding individual studies, it was found that The study by Lv et al. (2019), may be the primary source of heterogeneity, and I² decreased from 97% to 89% after removing the literatures. Due to the limited number of studies included in this analysis, it is speculated that this study had drug administration before ischemia, while the other two studies were administered after ischemia, which ultimately led to heterogeneity. Nonetheless, the findings continue to support the ability of Sal B to decrease the number of TUNEL-positive cells following acute ischemic stroke. See Figure 9.

FIGURE 9

3.5 Publication bias

Publication bias was assessed for infarct size using a funnel plot. The results showed that the points on the funnel plot were asymmetrically distributed along the centerline, indicating the presence of publication bias. See Figure 10.

FIGURE 10

4 Discussion

In addition, we analyzed and summarized other studies that met the criteria for “Sal B in acute ischemic stroke” but could not be combined for analysis. The results showed that Sal B also ameliorated acute ischemic stroke damage by: ① Anti-excitotoxicity: Excessive accumulation of glutamate in the intercellular space is the main source of neurotoxic reactions. The results showed that Sal B can significantly reduce the content of glutamate in brain tissue to inhibit excitatory amino acid toxicity and play a neuroprotective role. ② Anti-platelet aggregation: Platelets are activated and aggregated to form a large number of thrombi to block blood vessels, resulting in insufficient blood and oxygen supply to brain tissue. The results showed that Sal B can effectively combat acute ischemic stroke by inhibiting platelet aggregation and reducing thrombosis. ③ Promoting angiogenesis: VEGF and its receptor molecule VEGFR can improve vascular permeability, promote the generation of cerebral blood vessels by promoting the proliferation and migration of vascular endothelial cells. The results showed that Sal B can promote angiogenesis in time by up-regulating the expression of VEGFR2 and VEGFA, thereby reducing acute ischemic stroke injury.

According to the included studies, 8 studies were administered 7 days to 10 min before cerebral ischemia, and 6 studies were administered immediately or 1 h after cerebral ischemia, both of which had a significant therapeutic effect. The concentration of Sal B between 10 and 192 mg/kg will play a better therapeutic effect, and the longer the treatment time, the more significant the effect. However, more studies are needed to confirm the optimal timing, dosage and duration of administration.

Limitations and future directions: (1) Some studies included in the meta-analysis were downgraded in quality due to lack of blinding during induction and uncontrolled temperature. (2) Given the limited sample size, further research is warranted. (3) It is necessary to further study the mechanism of Sal B. (4) At the same time, better administration timing, the optimal dose and treatment time of Sal B should be understood to improve the efficacy of anti-ischemic stroke.

5 Conclusion

In conclusion, this study highlights the significant therapeutic potential of Sal B in treating acute ischemic stroke. Sal B can reduce infarct size, improve neurological deficit symptoms and reduce brain edema by anti-oxidative stress, anti-inflammatory response, anti-apoptosis, improving energy metabolism and stabilizing ion balance, thus achieving neuroprotection. It has great potential in the treatment of acute ischemic stroke.

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