Research progress on pharmacological effect of Salvianolic acid for injection in post-stroke depression

Wen Gu ， Li Wang

The Second Hospital of Shanxi Medical University

Keywords:

ABSTRACT

Stroke has become the second leading cause of death in the world, causing 6.3 million deaths in 2015[1]. Post-stroke depression (PSD) is one of the most common affective disorders that occurs after acute cerebrovascular injury, which seriously affects the neurological recovery and rehabilitation activities of survivors of stroke and significantly increases the mortality rate, the disability rate and the recurrence rate of stroke, placing a heavy burden on families and society[2]. The etiology of PSD is not clear. It involves a series of complex mechanisms. Inflammatory response, apoptosis, neurotrophic factors, and neurotransmitters may all play important roles, and there is no effective treatment. Currently, selective 5-HT reuptake inhibitors (SSRIs) or 5-HT and NE reuptake inhibitors (SNRIs) are commonly used to improve PSD symptoms in clinical practice. They are effective in preventing and treating PSD clinically, but the exact effect has not yet been proved. What is more, it has been confirmed that these drugs may increase the risk of myocardial infarction and cerebral hemorrhage[3]. Recent studies have found that Salvianolic acid for injection(SAFI) is effective both in stroke and depression [4,5,6] and may become a new drug for the treatment of PSD. This study summarizes the relationship between SAFI and PSD in order to provide a basis for clinical diagnosis and treatment of PSD.

1.Pharmacological effects of SAFI

SAFI is a freeze-dried powder injection produced exclusively by Tianshili pharmaceutical Co. Ltd. (Tianjin, China), which is extracted from traditional Chinese medicine Salvia miltiorrhiza. The main chemical components of SAFI are water-soluble phenolic acids such as salvianolic acid A (SAA), salvianolic acid B (SalB), salvianolic acid D (SalD), rosemary acid, and oxalic acid. However, SalB is the the highest and most active substance of the composite component, which can directly penetrate the blood-brain barrier and comprehensively protect the brain nerves[7]. SAFI is currently mainly used as an adjuvant treatment for mild to moderate cerebral infarction, which can effectively improve the symptoms of neurological deficits. The clinical effect is significant and the safety is high. A large number of experiments have confirmed that in many diseases such as heart, brain, liver, and kidney, SAFI has the functions of anti-inflammatory in vivo and in vitro, anti-oxidative stress, and anti-apoptotic[8]. It has been discovered that SAFI can significantly improve its depression behavior in a mouse model of depression induced by chronic unpredictable mild stimulus (CUMS)[6], therefore it may become a new type of antidepressant for choice.

2. SAFI and stroke

2.1 SAFI regulates inflammatory response in stroke

The inflammatory response is thought to be central in the process of cerebral ischemia-reperfusion injury. After cerebral ischemic injury, the inflammatory cells in the blood quickly migrate to the area of ischemic infarction, releasing a large number of inflammation cytokines, such as TNF-α, IL-1β, and IL-6. Guo et al. has found that SAFI can directly inhibit the expression of inflammation cytokines including IL-1β, IL-6, and TNF-α in their experimental studys[9,10]. Mccann et al. discoverd that stroke is associated with neuroinflammation disorders in their meta-analysis[11]. In the early stage of ischemic stroke, microglia and astrocytes are activated, a large amount of cytokines, chemokines and adhesion molecules are secreted, which induce the cascade of inflammation, leading to neuronal necrosis and reactive oxygen species. Microglia are targets of inflammatory mediators and are involved in the regulation of inflammatory responses. Wang et al. used a co-culture system of neurons and microglia to confirm that the cytoprotective effect of SAFI is due to its ability to inhibit inflammatory factors released by microglia[12]. Astrocytes are an important part of the bloodbrain barrier. Increased release of TNF-αin stroke can lead to microvascular dysfunction. SAFI can reduce the expression of TNF-α, inhibit the activation of astrocytes, and thus protecting the integrity of the blood-brain barrier[13]. The results of clinical studies indicate that the level of high-sensitivity C-reactive protein (hs-CRP) has decreased significantly after using SAFI to treat acute cerebral infarction. The mechanism may be related to the inhibition of adhesion molecules in the body and the improvement of cerebral ischemia-reperfusion-induced inflammation response[14].

2.2 SAFI regulates BDNF in stroke

Brain-derived neurotrophic factor (BDNF), a key regulator of brain activity, is widely expressed in hippocampal neurons. The expression of BDNF can induce dendritic growth, regulate synaptic plasticity and repair damaged neurons, which has an important impact on the survival and maintenance of neurons[15]. Chen et al. showed that BDNF can reduce the apoptosis of ischemic neurons, effectively prevent ischemic brain injury, and play an important role in the regeneration of hippocampal neurons [16]. Cortical neuron culture system under glucose and oxygen deficiency reperfusion (OGD/R) has been widely used to simulate ischemia /reperfusion injury effect on ischemic cerebrovascular disease in vitro, Wang et al. used this model to reveal that SMND-309(the active ingredient derivatives of SAFI) can reverse the low level expression of BDNF caused by OGD/R by activating the CREB/BDNF pathway, having a neuroprotective effect[17].

2.3 SAFI regulates apoptosis in stroke

Apoptosis is one of the main mechanisms of cell damage caused by ischemia-reperfusion[18], and oxidative stress is considered to be the main factor leading to neuronal apoptosis. After ischemia-reperfusion injury, mitochondrial pores are opened and electrochemical gradients are decoupled, which leads to the release of reactive oxygen species. As an antioxidant, SAFI can scavenge these free radicals and superoxide anions [19]. Within 24 hours of stroke, SAFI can protect the blood-brain barrier by reducing oxidative stress and apoptosis through the p65 NF-KB inflammatory waterfall and p25/Ckd5 (apoptosis-associated kinase) -related apoptosis pathways[20]. Lv et al. found that SalB significantly increased Bcl-2 expression and decreased Bax expression in experimental stroke rats, and the SIRT1 pathway played a key role in this process[21]. Another study signified that apoptotic cells increased significantly after treatment of umbilical vein endothelial cells (HUVEC) with H202, while CtyC and Caspase-3 levels in cytoplasm increased significantly after treatment with SalB [22].

3. SAFI and depression

3.1 SAFI regulates inflammatory response in depression

Clinical and preclinical studies have demonstrated that neuroinflammation is one of the major pathophysiological processes of depression[23]. Elevated levels of inflammation cytokines (such as TNF-α, IL-1 and IL-6) are causally related to various aspects of depression[24]. In animal experiments, chronic stress can increase secretion of microglia, leading to a large number of central and peripheral inflammation cytokines being released, which leads to to depression[25]. Injecting SalB for 3 consecutive weeks can significantly reduce the concentration of these inflammation cytokines, mainly due to the anti-inflammatory effects of SalB[26]. Further research by Zhang et al. found that after the administration of SalB, the number and area of microglia did not change, but the microglia phenotype changed from M1 to M2[27].

3.2 SAFI regulates BDNF in depression

Chronic chronic stress can damage the hippocampal pyramidal neurons and cause cognitive decline[28], while atrophy and aplastic disorders of hippocampal neurons are closely related to the development of depression symptoms[29]. Zhang et al. found that the hippocampal neuron morphology was not significantly affected and the expression of BDNF at the gene and protein levels did not significantly decrease after SAFI treatment in the chronic stress rat model, indicating that SAFI can prevent hippocampal neuron damage after chronic stress[30]. Human cadaver and animal studies have also shown that the inhibition of hippocampal neurogenesis is a major cause of depression[31]. Artificial SalB treatment can promote nerve regeneration, and this process is supported by neurotrophic factors such as BNDF and IGF-1[32]. Further studies have verified that H2O2 can induce the expression of BDNF in bone marrowderived neural stem cells (BM-NSCs), and treatment with SalB can further significantly increase BDNF production[33].

3.3 SAFI regulates apoptosis in depression

There is little evidence about the research of SAFI in regulating apoptosis in depression. Only Zhang et al. found that SalB can improve neuronal apoptosis in prefrontal cortex and hippocampus caused by chronic stress, reduce hippocampal atrophy and decrease cell density. However, these apoptotic cells is closely related to microglia activation[6].

4. SAFI and PSD

The etiology of PSD is relatively complicated, and the theory of immune inflammatory response has been the focus of scholars' research. Inflammation cytokines can increase the gene expression of indoleamine 2,3-dioxygenase and tetrahydrobiopterin, altering the synthesis and activity of serum dopamine, 5-HT, and norepinephrine, and increasing their reuptake, reducing the synaptic space transmitter concentration. What is more, they can also regulate the HPA axis, thus affecting the expression of serum adrenocortical hormones and cortisol[34,35], inhibiting the regeneration of hippocampal neurons, reducing the neuroplasticity of prefrontal cortical, leading to PSD[36]. Kim used alleles to determine that high expression of pro-inflammatory cytokines (IL-1β, TNF-α) and low expression of anti-inflammatory cytokines (IL-4, IL-10) are associated with PSD[37], which further reflects that inflammatory cytokines play an important role in the occurrence and development of PSD. In addition, the onset of PSD is closely related to the expression of BDNF. Clinical studies have shown that serum BDNF levels are independent predictors of PSD within 3 months after stroke. The lower the BDNF level at admission is, the greater the risk of subsequent PSD is[38,39]. Animal experiments also showed that the relative expression of BDNF protein and mRNA in hippocampus tissue of PSD model rats was reduced[40]. AS for the relationship between PSD and apoptosis, Ji Yunjian et al. found that the serum expression of Bax, Fasl, Fas, and Caspase-3 in patients with PSD significantly increased. After drug treatment, the expression of these apoptotic factors decreased and depression behavior was significantly improved[41].

The inflammatory response is the bridge between stroke and PSD. SAFI can directly or indirectly inhibit the secretion of inflammation cytokines or regulate the expression of microglial cells in stroke and depression[26,42], and may be involved in the occurrence and development of PSD; BDNF is one of the targets of SAFI and is also one of the important factors in the pathophysiology of PSD. SAFI can improve the symptoms of stroke and depression by regulating the expression of BDNF and its receptor protein[16,30], suggesting that SAFI will also play a better role in the treatment of PSD. Given that SAFI has the functions of strong anti-oxidative stress and antiapoptosis[21], suggesting that SAFI can regulate neural cell apoptosis through various pathways and improve hippocampal neuron damage. PSD is the main complication of cerebrovascular disease, and has more basis for organic lesions than depression. After the stroke, the tissue is damaged, and a large number of excitatory amino acids and oxygen free radicals are released, which exacerbates oxidative stress. Oxidative stress is closely related to inflammatory response or apoptosis, so the anti-oxidative effect of SAFI also plays an important role in its anti-inflammatory and anti-apoptotic effects. All in all, the anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects of SAFI may be due to its improved microenvironment for neuronal survival, playing a neuroprotective role. In addition, SAFI can significantly increase the expression of BDNF and its receptors, which is very important for the growth and development of axons. Furthermore, SAFI also has a significant regulatory effect on the hypothalamus-pituitary-adrenal axis.

5. Summary and Outlook

In summary, the pathogenesis of PSD is very complicated, and the clinical manifestations of PSD are also the result of multiple effects. Therefore, the treatment of PSD also seeks a combination of multiple targets and multiple effects. At present, research on the role of SAFI in PSD is still in its infancy. SAFI has multiple excellent characteristics and has also shown good antidepressant effects in a large number of basic experiments. It is expected to become a new type of antidepressant for the treatment of PSD, but a lot of research is still needed to systematically carry out many levels of detail argument. It is believed that SAFI will bring more therapeutic prospects with the development of neuroscience and medicine.