Effects of Xingnaojing Injection on Cerebral Neurological Function and ET-1, hs-CRP and TNF-α Levels in Elderly Patients with Acute Cerebral Infarction

Sun Tingting (孫婷婷), Chen Ming (陳 銘)

Xuancheng People's Hospital, Xuancheng 242000, China

ABSTRACT OBJECTIVE: To observe the effects of Xingnaojing Injection on the function of cranial nerves and the level of ET-1,hs-CRP and TNF-α in elderly patients with acute cerebral infarction. METHODS: A total of 86 elderly patients with acute cerebral infarction were randomly divided into observation group and control group. The 43 cases in the control group were treated by conventional Western medicine, and 43 cases in the observation group were treated by Xingnaojing injection on the basis of the treatment in control group. After 2 weeks' treatment in Xuancheng People's Hospital of Anhui Province, the neurological function (NIHSS score and MMSE score), daily living ability (BI Index score and ADL score),laboratory indicators (hs-CRP, ET-1, TNF-α) of the 2 groups before and after the treatment were observed and compared,the total clinical effectiveness of the 2 groups were compared. RESULTS: The total effective rate was 88.4% in the observation group, which was significantly higher than that in the control group (62.8%) (P ＜ 0.05). The NIHSS scores in the 2 groups were both significantly increased after the treatment (P ＜ 0.05) while the MMSE scores were significantly decreased (P ＜ 0.05) in the 2 groups, and the scores' improvement in the observation group was significantly higher than that in the control group (P ＜ 0.05). The BI score and ADL score were significantly increased in the 2 groups after the treatment (P ＜ 0.05), and the improvements were obvious in the observation group. The levels of ET-1, hs-CRP and TNF-α in the 2 groups were significantly decreased after the treatment (P ＜ 0.05), and the indexes in the observation group were significantly lower than that in the control group (P ＜ 0.05). CONLUSIONS: Xingnaojing injection can reduce the levels of serum ET-1, hs-CRP and TNF-α, as well as the degree of neurological deficit in the treatment of elderly patients with acute cerebral infarction. It is also helpful for the prognosis and outcomes of patients with cerebral infarction.

KEYWORDS: Senile acute cerebral infarction; Xingnaojing injection; Cranial nerve capacity; Inflammatory factor; Endothelial functions

Acute cerebral infarction, also known as acute ischemic stroke, refers to the disorder of brain blood supply caused by cerebral vascular stenosis or occlusion.The local brain tissue softening or necrosis due to ischemia and hypoxia causes acute cerebrovascular disease with neurological damage and a series of neurological symptoms[1]. The disease is clinically prevalent in elder people. Studies have shown that over the age of 40, the incidence of cerebral infarction will double for adding every 5 years of age, and most patients with cerebral infarction have a rapid onset and almost without precursors. The signs of focal nerves will quickly reach the peak in a few minutes to a few hours, although the patients will not completely lose their consciousness.The middle cerebral artery or internal carotid artery trunk is easy to cause serious cerebral edema due to siltation,which may cause cerebral hernia and even threaten patients' life safety[2]. The clinical studies have confirmed that timely establishment of collateral circulation pathway, improving blood flow in the penumbra after cerebral ischemia, and protecting brain neuron cells is the key to improve the prognosis of patients with acute cerebral infarction[3]. At present, Western medicine provides thrombolytic therapy for patients with acute cerebral infarction who are in the onset time window and meet the indications. Patients who have exceeded the time window or have thrombolysis contraindications are given anticoagulant and neuroprotective agents treatment.Although these treatments have certain effects, Western medicine treatment mechanism is relatively simple, and is difficult to exert a stable and long-lasting effect on the variability and complexity of the elderly patients with acute cerebral infarction. Traditional Chinese medicine (TCM) has a long history of understanding and researching acute cerebral infarction. It believes that qi and blood disorder, yin and yang disharmony are the root causes of this disease. Wind, fire, stasis,phlegm and deficiency are the most critical processes in the course of disease progression. Besides, the effects and transformation of pathological factors result in this repeated and persistent disease. Xingnaojing injection is a water-soluble injection prepared on the basis of Angong Niuhuang Pill, a kind of traditional Chinese medicine, by modern technology. It can be used for stroke coma, traumatic headache, alcoholism and heart attack,conscious coma, headache, nausea and other symptoms caused by disordered qi and blood and blockade of cerebral vessels. It can resuscitate and refresh the brain,and has been widely used in the rescue of various critical illnesses. From January 2016 to June 2017, the author treated 43 elderly patients with acute cerebral infarction by Xingnaojing injection with satisfactory outcomes.

CLINICAL MATERIALS

General resources

A total of 86 patients with acute cerebral infarction admitted to our hospital during above period were selected.The diagnosis of Western medicine complies with the provisions of Guidelines for the diagnosis and treatment of acute ischemic stroke in China 2010 for acute cerebral infarction[4]: rapid onset and the disease duration is less than 2 weeks, most of the patients had focal neurological deficits, the clinical symptoms and signs were maintained for several hours, brain CT or MRI confirmed responsible lesions, cerebral hemorrhage was excluded. TCM syndrome differentiation is in line with the provisions of the blood stasis certification in Clinic terminology of traditional Chinese medical diagnosis and treatment - Syndromes[5]:blood stasis, abnormal feelings on the limbs, squamous and dry skin, stabbing pain, ecchymosis under the skin,and refusing to pressure. The tongue was dark purple with ecchymosis and petechiae, and the pulse was deep or unsmooth. The patients were aged between 60 and 85 years old, and the sub-types of NIHSS scored 5 to 25 points.They were fully informed of this clinical trial and signed informed consent. The patients were excluded with severe primary diseases of liver, kidney, cardiovascular system,hematopoietic system, gastrointestinal system, or recent acute infectious diseases, complicated by multiple cerebral infarction, hemorrhagic cerebral infarction, cerebellar infarction, brain stem infarction, malignant tumors and mental illnesses, and therapeutic failure results from the inability to strictly follow the prescribed treatment. The enrolled patients were randomly divided into 2 groups:43 patients (25 males and 18 females) in the observation group, aged 60 - 85, the duration of disease was 3 h-13 d.43 patients (27 males and 16 females) in the control group,aged 61-83, the duration of disease was 5 h-15 d. The differences of gender, age, disease duration between the 2 groups had no statistical significance (P ＞ 0.05).

METHODS

The control group was given conventional Western medicine treatment by peroral Aspirin Entericcoated Tablets (SFDA approval number: H10960304;manufacturer: Shenyang Aohua Pharmaceutical Co.,Ltd.; specification: 50 mg), 100mg/time, 2 times/d,and Adaravon (SFDA approval number: H20110007;manufacturer: Yangzhou Pharmaceutical Co., Ltd.;specification: 20 mL: 30 mg) by injection, taking 30 mg into 100mL normal saline (0.9%), 2 times/d; Low Molecular Weight Heparin (SFDA approval number:H20030428; manufacturer: Qilu Pharmaceutical Co., Ltd.;specification: 0.2 mL/2500 IU) by subcutaneous injection,5000 U/time, 1 time/12 h; if necessary, intravenous drip 15% - 25% Mannitol Injection (SFDA approval number: H20043784; Sichuan Kelun Pharmaceutical Co.,Ltd.; specification: 250 mL: 50g), 0.25 - 2 g/(kg?time),finishing within 1 hour. All the treatments above last for 2 weeks. On the basis of the treatment in the control group,the observation group was given Xingnaojing Injection(SFDA approval number: Z53021639; manufacturer: Dali Pharmaceutical Co., Ltd.; specification: 10 mL), adding 20 mL into 250 mL saline (0.9%) by intravenous infusion,1 time/d for continuous 2 weeks.

Observation index

The evaluation criteria were made according to the references[6]. Recovery: After the treatment, the patient's functional deficit score decreased more than 91%, the degree of disability was 0. Markedly effective: After the treatment, the patient's functional deficit score decreased 46% to 90%, the degree of disability was 1 to 3. Effective:After the treatment, the patient's functional deficit score decreased 18% to 45%. Invalid: After the treatment,the patient's functional deficit score decreased less than 18%, or even increased. Recovery + markedly effective +effective = total effective.

Neurological function: The NIHSS scale was used to evaluate the neurological impairment before and after the treatment. The score ranged 0 – 45, the higher the score is,the more serious the nerve injury is. The simple intelligence scale (MMSE) was used to evaluate the cognitive status before and after the treatment. The score ranged 0 - 30, the higher the score, the higher the cognitive function.

Assessment of daily living ability: Barthel index(BI) was used to assess the improvement of daily living activities before and after the treatment. The score ranged 0 - 100, the higher the score, the stronger the self-care ability. The daily living ability scale (ADL) was used to evaluate patients' ability in daily living activities before and after the treatment. It mainly included 6 items with scores ranging 0 – 100. The higher the score, the higher is the ability in daily living activities.

Laboratory indicators: A total of 2mL of fasting peripheral venous blood of the patients before and after the treatment were taken respectively. After centrifugation, the level of high-sensitivity C-reactive protein (hs-CRP) was determined by immunoturbidimetry.While endothelin-1 (ET-1) and tumor necrosis factor α (TNF-α) were measured by enzyme-linked immunosorbent assay. All the operations were performed in strict accordance with the instructions.

Statistical methods

Statistical analysis was performed by statistical software SSPS 22.0. The measurement data was expressed by x–±s, and the t test for comparison. The count data was represented by n (%), and χ2test for comparison. P ＜ 0.05 indicates statistically significant.

RESULTS

Comparison of clinical effects in the 2 groups after the treatment

After the treatment, the total effective rate of the observation group was 88.4%, which was significantly higher than that of the control group (62.8%) (P ＜ 0.05). See Table 1.

Comparison of neurological score in the 2 groups before and after the treatment

Before the treatment, there was no significant difference between the 2 groups in NIHSS score and MMSE score (P ＞ 0.05). After the treatment, the NIHSS scores of both groups were significantly increased(P ＜ 0.05), and the MMSE scores were significantly decreased (P ＜ 0.05). The improvement of the above scores in the observation group was significantly higher than that of the control group (P ＜ 0.05). See Table 2.

Comparison on evaluation of abilities of daily living in the 2 groups before and after the treatment

Before the treatment, there was no significant difference in ADL scores between the 2 groups (P ＞ 0.05).After the treatment, the BI scores and ADL scores of the 2 groups were significantly increased (P ＜ 0.05) and the improving degree in the observation group was significantly higher than that in the control group (P ＜ 0.05). See Table 3.

Comparison on levels of ET-1, hs-CRP and TNF-in the 2 groups before and after the treatment

Before the treatment, there were no significantdifferences in serum ET-1, hs-CRP and TNF-α levels between the 2 groups (P ＞ 0.05). After the treatment,serum ET-1, hs-CRP and TNF-α were significantly decreased in both groups (P ＜ 0.05), and the decreasing degree in the observation group was significantly higher than that of the control group (P ＜ 0.05). See Table 4.

Table 1. Comparison of clinical effects in the 2 groups after the treatment cases (%)

Table 2. Comparison of neurological score in the 2 groups before and after the treatment (x–±S, score)

Table 3. Comparison on evaluation of abilities of daily living in the 2 groups before and after the treatment (x–±S, score)

Table 4. Comparison on levels of ET-1, hs-CRP and TNF-α in the 2 groups before and after the treatment (x–±S, score)

DISCUSSION

Acute cerebral infarction refers to the suspend of the blood flow caused by occlusion of blood supply to the brain, while the new collateral circulation has not yet been established, resulting in ischemia, hypoxia,brain function damage, and a series of cerebrovascular diseases signed as neurological deficits. Modern medical research believes that vulnerable arterial intimal changes including unstable plaque, endometrial ulcer are the main risk factors for cerebral infarction. The plaque shedding or a large number of microemboli formation induced by hemodynamic abnormalities are the main pathogenesis of infarction[7]. In addition, clinical studies have shown that a large number of inflammatory mediators and in flammatory cells play important roles in the pathogenesis of acute cerebral infarction[8]. ET-1 is a strong vasoconstrictor substance, which can effectively respond to vascular endothelial function. If the release of ET-1 is increased, it will cause vasoconstriction and induce thrombosis. Therefore, ET-1 is in a thrombotic chain reaction. It plays an important role in the initial stage[9]. Hs-CRP is an acute phase protein of hepatocyte synthesis when the body is inflammatorily stimulated.Under normal physiological conditions, the expression level of hs-CRP is low, while it will rise abnormally when the body tissue is infected or damaged. Pence S et al[10]have confirmed that the expression level of serum hs-CRP is significantly positively correlated with the severity of cerebrovascular diseases, and can be used as an important indicator to evaluate the prognosis of patients with cerebral infarction. TNF-α is a polypeptide cytokine secreted by mononuclear macrophages. It can up-regulate the expression levels of leukocyte adhesion molecules and vascular endothelial cells, and promote the activation of lymphocytes into the brain, thereby aggravating the cerebral ischemic inflammatory response. Wu Yingman et al[11]have confirmed that the expression level of serum TNF-um TNF-NF-cules and vascular endothelial cells,and promote the activation of lymphocytes into the brain,thereby aggravate blood-brain barrier in local tissues of cerebral ischemia and the appearance of mononuclear macrophages from the periphery blood into the brain tissue. After an acute cerebral infarction, the cerebral neuroblast of the patient will gradually become apoptotic within a few minutes. However, within a certain period of time, some cerebral neuroblast still survives surrounding some dead nerve cells. If the blood vessels are re-treated within the time window, it is possible to save this part of the cerebral neuroblast, while once the time window is exceeded, the clinical morbidity and mortality of the patients will be greatly improved.

Acute cerebral infarction belongs to the category of "stroke" in traditional Chinese medicine (TCM).TCM believes that the disease is located in the brain and is closely related to the heart, liver, spleen and kidney.The causes of this disease are the disharmony of yin and yang, lacking of qi and blood. Wind, fire, phlegm and stasis are the most important pathological factors in the pathological process. This disease belongs to the syndrome of the deficiency of the root while excess in the superficiality. At the early stage of the disease, the evil qi is rising, and the mainly manifestation is excess of the superficiality. With the development of the disease,the vital qi and the evil qi intersected with each other.To the late stage of the disease, the vital qi becomes too deficiency to eliminate pathogens. The patients show different degrees of sequelae. According to the abovementioned etiology and pathogenesis, clinical treatment should be based on the principle of extinguishing wind and removing obstruction in collaterals, refreshing the mind and resuscitation, promoting blood circulation for removing blood stasis. Xingnaojing Injection is a new type of traditional Chinese medicine injection developed on the basis of Angong Niuhuang Pill. It consists of Moschus, Fructus Gardeniae, Radix Curcumae and Borneolum Syntheticum. Among them, Moschus can awaken the spirit and resuscitate patients, promote blood circulation for removing obstruction in collaterals,detumescence and relieve pain. Fructus Gardeniae has the effects of clearing heat and promoting diuresis,purging fire and detoxifying. Radix Curcumae has the functions of clearing away heart-fire and relieving qi stagnation, promoting blood circulation for removing blood stasis, regulating qi-flowing for relieving pain.Borneolum Syntheticum can awaken the spirit and resuscitate patients, clear the heat and relieve the pain.All kinds of medicines are used together to awaken patients from unconsciousness and resuscitation, promote blood circulation for removing blood stasis, extinguish wind and remove obstruction in collaterals. Modern pharmacological studies have shown that Moschus can directly act on the central nervous system through the blood-cerebrospinal fluid barrier, effectively improving the hypoxia tolerance of the central nervous system. In addition, Moschus can effectively reduce the level of aspartate, the excitatory neurotransmitter, during cerebral ischemia, improve the level of inhibitory neurotransmitter and inhibit excitatory amino acid toxicity, thereby avoiding secondary neuronal damage following cerebral ischemia[12]. Fructus Gardeniae contained in geniposide can delay biochemical reactions in rats with femoral artery thrombosis occlusion by affecting the activity of cerebral thrombosis and thrombocyte activity and ultimately play an antithrombotic effect[13]. The water extract of Radix Curcumae can effectively dissolve fibrinogen, which helps promote blood clotting and wound healing. In addition, Radix Curcumae also has a function of anti-inflammatory and anti-oxidative stress activities[14]. Borneolum Syntheticum can bidirectionally regulate the central nervous system, protecting cardiocerebral, anti-inflammatory, anti-bacterial and relieving pain[15]. A large number of clinical studies have confirmed that Xingnaojing Injection can reduce cerebral vascular permeability, inhibit endogenous pyrogen in cerebrospinal fluid and the apoptosis of neuroblast,reduce cerebral edema, improve cerebral circulation,and protect ischemic penumbra of patients with acute cerebral infarction[16,17]. Animal experimental studies have confirmed that Xingnaojing Injection can significantly improve cerebral ischemia, anoxia, and edema after brain injury in rats, and also can effectively avoid dissimilation of excitatory amino acid, and protect the ultrafine parts in cortical tissue of cerebral ischemia rats[18]. In addition,Xingnaojing Injection can effectively inhibit the cytokinemediated inflammatory responses including TNF, IL-6 and IL1-6 and IL1-IL-6 and IL1-hem redoblast, reduce ischemia-reperfusion injury in rabbits.

The results of this study showed that the total effective rate of the observation group after the treatment was significantly higher than that of the control group, and the improvement of neurological function, daily living ability and laboratory index were significantly higher than the control group. It is suggested that Xingnaojing Injection can inhibit the synthesis and release of in flammatory mediators by decreasing the levels of serum ET-1, hs-CRP and TNF-α, thereby reducing the degree of neurological deficits and contributing to the prognosis of patients with cerebral infarction.