Cerebrovascular disease is one of the major diseases that leads to human fatalities. Haemorrhagic brain damage and ischaemic brain damage lead to different degrees of advanced neurocognitive dysfunction (Zhang, 2012). With the ageing of the population in China, the incidence of vascular cognitive impairment (VCI) is increasing annually, and exerts a significant burden on the society and family. Ischaemic cerebrovascular disease is the most common amongst the VCI diseases, and ameliorating cognitive dysfunction caused by this disease is one of the main challenges faced by neurologists. Continuous apoptosis of brain cells, abnormal cerebral vascular microcirculation, and a lack of proper blood circulation have been implicated in the pathophysiology of VCI (Han et al., 2014). Anticholinergic drugs are clinically applied to treat VCI, though this practice has not gained universal acceptance. The key mode of treatment in VCI aims to promote cerebral vasodilation, increase blood oxygen content, and promote neuronal viability (Guo et al., 2013; Wang H. R. et al., 2014).

Traditional Chinese medicine has achieved remarkable curative effects in VCI patients as evidenced by multi-level and multi-dimensional studies (Hou et al., 2009). Danshen preparations have been frequently used in this regard. In recent years, a number of studies have shown that Danshen preparations have multiple biological activities including natural antioxidant properties, scavenging of a variety of oxygen free radicals, and activation of antagonists of platelet-activating factor. Danshen preparations can also significantly dilate cerebral vessels and improve the symptoms of cerebral ischaemia and hypoxia. The active ingredients in Danshen preparations have been shown to have a variety of neuroprotective and restorative effects which help maintain the blood–brain barrier, reduce cerebral oedema, improve energy metabolism, exert antioxidant, anti-inflammatory, and anti-apoptotic effects, promote angiogenesis, and exert therapeutic effects in VCI. Danshen preparations have been applied in various forms including Danshen injections, Danshen tablets, Sodium Tanshinone IIA Sulfonate, Danshen dripping pill, Danshen granules, and Danshen capsules. Tanshinone can promote the proliferation and differentiation of neural stem cells cultured in vitro and can also promote the proliferation of endogenous neural stem cells and improve neurological function after ischaemia (Chen et al., 2011).

Danshen preparations are widely used in traditional Chinese medicine and are economical and efficient blood stasis-removing agents (Wu et al., 2015). These preparations have been in use since many years, and their application has shown an increasing trend annually; reports of adverse events have also gradually increased. The most common adverse reactions were allergic reactions and abnormal bleeding. Tanshinone and acidic crystals are amongst the active ingredients in Danshen preparations. These components may function as haptens and cause allergic reactions after binding to plasma proteins in the body. The tannins contained in Danshen preparations cannot be effectively removed by the current methods of preparation. The tannins form macromolecular complexes after binding to the amino groups in plasma proteins, causing allergic reactions. Danshen preparations contain a number of insoluble particles that may occlude local blood vessels, which frequently leads to phlebitis and thromboembolic events (Gong, 2021).

In this study, we retrieved all publications (published prior to December 2021) reporting on RCTs of Danshen preparations used in the treatment of VCI; we aimed to evaluate the clinical efficacy and safety of Danshen preparations in the treatment of VCI, and provide references for the clinical treatment of VCI.

We performed a MA according to the Cochrane Handbook for Systematic Reviews of Interventions (Shuster, 2011); the results are presented as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Moher et al., 2009). Our MA has been registered on PROSPERO (registration number: CRD42022299993). The research followed guidelines of the Declaration of Helsinki and Tokyo for humans, and was approved by the institutional human experimentation committee or equivalent, and that informed consent was obtained, ethics review approval document no. 2022NL-010-02.

The existing clinical intervention approaches for VCI can be categorised into two types: drug-based and non-drug-based. Non-drug-based therapy includes cognitive behavioural therapy, cognitive sandplay therapy, and cognitive dialectical behaviour therapy. Drug-based interventions include treatment with donepezil, which is a hexahydro pyridine derivative and a second-generation highly selective acetylcholinesterase inhibitor (Fan et al., 2020). This drug can specifically inhibit acetylcholine-degrading enzymes in the brain, and exhibits a bioavailability of 100% for oral formulations. Oxiracetam is a nootropic drug. This drug also improves cognitive dysfunction; it can cross the blood–brain barrier and is reported to promote the recovery of cerebral cortex and hippocampus nerve cells and ameliorate nerve blocks and metabolism (Shuster, 2011; Wang et al., 2020). Piracetam can act directly on the cerebral cortex to activate, protect, and repair brain nerve cells. It is mainly applied in treating memory loss and mild to moderate brain dysfunction. Piracetam can also prevent damage to the brain function caused by physical and chemical factors, improve reverse amnesia caused by ischaemia, effectively enhance memory retention, and improve learning ability. Vinpocetine can increase the oxygen content of brain tissue fluid in patients. It can improve the activity of haemoglobin, induce haemoglobin to release a large amount of blood oxygen, reduce blood viscosity, and improve brain function. Neural stem cell transplantation is a novel method for the treatment of many neurological diseases, especially ischaemic cerebrovascular disease. Several studies have demonstrated that exogenous neural stem cell transplantation can improve neurological function in rats after ischaemia (Ye et al., 2005; Liu et al., 2007). However, this method has not yet been widely used clinically due to issues regarding the purification of neural stem cells, transplant rejection, and other ethical issues. At present, there is no single drug nor non-drug therapy that can achieve a satisfactory curative effect, and the clinical treatment of VCI urgently needs to be improved. Danshen preparations can be used as complementary therapy in this regard.

It has been reported that traditional Chinese medicines used for invigorating the blood and removing blood stasis can have curative effects in many ischaemic diseases (Wang et al., 2017). Danshen is the root and rhizome of the Lamiaceae plant Salvia miltiorrhiza. It is bitter and slightly cold in nature and is attributed to the heart and liver meridians. It facilitates blood circulation and removes blood stasis, dredging channel and alleviating pain, clearing the mind, eliminating vexation, cooling the blood, and eliminating carbuncle. The medicinal value of Danshen has been known in China for more than 600 years, and it is an important component of traditional Chinese medicine. Southern Yunnan Materia Medica records that Danshen can “nourish the heart, tranquillise and sedate the mind, and resolve poor memory, restlessness, palpitation, and insomnia.” The chemical components of Danshen include tanshinones, cryptotanshinones, and salvianolic acids. Tanshinones are amongst the main active ingredients, and include tanshinone IIA and salvianol. The main active monomers of salvianolic acids are salvianolic acid A and salvianolic acid B (Jiang and Shi, 2017). Tanshinone can promote the proliferation and differentiation of neural stem cells in vitro (Xia et al., 2003; Yu et al., 2004), promote the proliferation of neural stem cells in the brain of rats with transient forebrain ischaemia, and improve neural function. Tanshinone IIA has effects on a variety of blood coagulation factors (Su et al., 2019). It has been reported to inhibit atherosclerosis, improve vascular smooth muscle function and collateral circulation in the ischaemic myocardium, inhibit neutrophil activation, reduce free radical levels, inhibit platelet aggregation, prevent thrombosis, and improve neural cell viability. This compound can also improve the memory and cognitive function in patients, restore their daily living ability, and prevent dementia; it is also reported to possess glucose-and lipid-lowering abilities (Jiang et al., 2019). Tanshinone IIA has been reported to improve learning and memory functions in VD rats. Combined with mesenchymal stem cells (MSCs), it can attenuate tau phosphorylation, enhance the activity of the central cholinergic system, reduce the generation of reactive oxygen species (ROS), and significantly enhance the activity of total superoxide dismutase (T-SOD) in the rat hippocampus. In addition, it can inhibit the apoptosis of hippocampal neurons by up-regulating the expression of BCL-2 and down-regulating the expression of BAX (Kong et al., 2017; Deyan et al., 2021). Tanshinone IIA sodium sulfonate is a derivative of tanshinone IIA and has high water solubility and bioavailability. It has anti-inflammatory, antioxidant, and anti-apoptotic effects (Cai et al., 2016). Moreover, it can improve the total antioxidant capacity, increase the level of superoxide dismutase, lower the levels of pro-oxidative products, and reduce neurological damage (Liu et al., 2010).

Salvianol can inhibit the mRNA expression of IL-1β, IL-6, and TNF-α, and inhibit the expression of mammalian Ste20-like kinase 1 (MST1) and the downstream transcription factor p-FOXO3. Accordingly, it improves working memory in VD rats and inhibits lipopolysaccharide (LPS)-induced apoptosis of hippocampal neurons (Yang et al., 2016). Salvianolic acid B ameliorates memory impairment in VD rats by increasing the level of insulin-like growth factor-1 (IGF-1) and the expression of P-AKT. Treatment with this compound promotes the attainment of a more compact morphology of neurons in the CA1 region, and a reduction in the apoptosis of these neurons (Ma et al., 2017). Salvia polyphenolate is a salvianolate compound extracted from Danshen; Salvia miltiorrhiza magnesium acetate is the main component herein. There are several advantages to this compound, as follows: its active ingredients have been identified, its quality is easy to monitor, its toxicity and side effects are limited, and its curative effect is stable (Chen et al., 2017). Salvia polyphenolate can directly cross the blood–brain barrier and act on mitochondria, ion pumps and other targets by increasing cerebral blood flow in the ischaemic area. It also has other functions as follows: prevents platelet aggregation, regulates intracellular Ca²⁺ concentration, inhibits cell apoptosis; it further exhibits anti-inflammatory and antioxidant properties s (Mi, 2013). Animal experiments have also confirmed (Wang and Wu, 2018) that salvianolate can increase ATPase activity, improve energy metabolism, and reduce excitatory amino acid content, thereby reducing cytotoxic oedema after cerebral ischaemia in mice; it is also reported to improve brain function, spatial learning, and memory. Additionally, salvianolate can decrease error rates in the step test, increase the delay time in the step test, and reduce the content of malondialdehyde (MDA) in the cortex, hippocampus, and striatum. This indicates that it can ameliorate the learning and memory impairment caused by cerebral ischaemia in mice (Wang, 2018).

This study used clinical efficacy, NIHSS, mRS, ADL, and MMSE as the main indicators of the effectiveness of Danshen preparations in VCI patients. According to the results of our MA, Danshen preparations have a positive effect in VCI patients, and can significantly improve neurological function and daily living ability. The NIHSS is the most widely used assessment tool for the predictive and prognostic evaluation of elderly patients with ischaemic cerebrovascular disease. This tool evaluates various parameters that reflect the neurological impairment of the patient including the patient’s state of consciousness, language skills, and motor status; this tool has good reliability and practicability (Hilz et al., 2011). The mRS is used to evaluate the recovery of neurological function in patients after a stroke. It has the advantage of providing strongly objective results and is not affected by education level (Weimar et al., 2002); thus, this scoring method overcomes the shortcomings and strong subjectivity of the NIHSS scale. The MMSE, developed by Folstein et al. (1975), is widely used in cognitive function screening and mainly evaluates functions such as orientation, memory, language, calculation, and attention. The MMSE takes a short time to complete and does not require a high education level. It has high sensitivity for evaluating cognitive impairment in moderate to severe dementia and impairment of multiple cognitive domains. MOCA, developed by Nasreddine et al. (2005), has a high screening sensitivity for cognitive impairment. It is designed to assess mental strength and mobility, but is also effective in assessing memory, language, thinking styles, and numeracy.

TNF-α, IL-6, and hs-CRP are commonly used indicators to assess the severity of inflammatory responses, and are considered to be closely related to the occurrence and development of VCI and VD (Zhang et al., 2020). IL-6 is a cytokine with various biological activities, and is an important inflammatory factor in the cytokine network. The abnormal release of this cytokine leads to metabolic disorders and functional impairment of cells in multiple organs of the body (Lu et al., 2000). hs-CRP is synthesised by stem cells in response to inflammatory stimuli such as microbial invasion or tissue damage, and is a non-specific phase protein secreted in the acute phase. It is commonly used as an indicator of the severity of inflammatory responses (Wang et al., 2015). hs-CRP participates in inflammatory responses and causes tissue damage by activating the complement pathway; it also promotes thrombosis. It has been reported that the measurement of hs-CRP levels at admission has an independent prognostic value in evaluating neurological deficits (Di Napoli et al., 2005); If inflammation persists, the protective effects evident in the acute phase may be converted to pro-inflammatory effects. Kuo et al. (2005) report that inflammatory markers can reflect the mechanism of cerebrovascular disease related to cognitive impairment, and changes in the levels of these markers can often be detected before the clinical symptoms of cerebrovascular disease appear. Elevated baseline hs-CRP levels suggest a direct toxic effect on neurons caused by long-term chronic inflammatory processes. The possible pathological mechanisms of hs-CRP include vascular damage caused by atherosclerosis, which further leads to frontal lobe circulation disorders, thereby affecting cognitive function (Liu, 2015). Inflammatory markers were used as secondary indicators in this study. Our MA suggests that Danshen preparations can alter the levels of the above-mentioned inflammatory markers associated with VCI. It is well known that cardiovascular diseases and tumour diseases are mostly caused by inflammation, and the anti-inflammatory activity of Danshen preparations can be widely used in the treatment of cognitive impairment patients with cardiovascular diseases or tumour diseases.

With the wide application of Danshen preparations in clinical practice, the number of reports of adverse reactions have increased. There is a lack of evidence-based studies that evaluate the efficacy and safety of Danshen preparations. This MA provides a comprehensive and complete reference for the clinical use of Danshen preparations. Our analysis showed that there was no significant difference in the occurrence of adverse reactions between Danshen preparation-treated and untreated groups. We believe that advancements in preparation technology have led to stricter quality control standards; which has led to a reduction in the occurrence of adverse reactions. However, it is also prudent to avoid the combined use of Danshen preparations with anticoagulants such as aspirin and warfarin, and strictly control the dose within a reasonable range.

This study reinforces the evidence that Danshen preparations have a significant therapeutic effect on VCI patients. Such preparations may lower inflammation and have beneficial effects on cognitive function in this patient population. Though our current study has some limitations, it is expected that further clinical trials will improve the level of evidence through stricter experimental designs, more comprehensive indicators, and by including large sample sizes.

MW (1966–), male, chief physician, doctoral supervisor, director of encephalopathy centre, Jiangsu Provincial Hospital of Chinese Medicine. Member of Stroke Society of Jiangsu Medical Association, deputy director of encephalopathy Professional Committee of Jiangsu Chinese Medicine Association. Standing committee member of Integrated Chinese and Western Medicine Branch of Chinese Stroke Association, Standing committee member of Integrated Chinese and Western Medicine Neurology of Chinese Medical Doctor Association, Member of Interventional Neurology of Chinese Research Hospital Association, visiting Scholar, Royal Melbourne Hospital, Australia.

YL and YY: conceptualisation, visualisation, and methodology. XC and NY: data curation and investigation. YL and NY: formal analysis. YL and YY: writing–original draft. YL and NY: developed pictures. YY and XC: developed tables. JL: writing– review and editing. MW and JL: supervision. All authors contributed to the article and approved the submitted version.

Project of Jiangsu Provincial Hospital of Chinese medicine (Y18004, Y19044, Y20025, and Y2019CX10); The Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions no. ZYX03JG035.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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