The therapeutic effect of combined therapy of hemopoietin and methylprednisolone in treatment of spinal cord ischemia-reperfusion injury of patient with cervical spondylotic myelopathy and its influence to the level of serum IL-1β, IL-1Ra and IL- 8

*Corresponding Author:

Lin Zhao
Department of Internal Care
Medical College of Yan’an University
Shanxi, 716000, China
E-mail: sss741a@163.com

Abstract

Purpose: To study thetherapeutic effect of combined therapy of hemopoietin and methylprednisolone in treatment of spinal cord ischemia-reperfusion injury and explore the its influence to the level of IL-1β, IL-1Ra and IL-8.

Method: 80 patients who had been accepted for cervical spondylotic myelopathy in our hospital during March 2014 to September 2017 were selected as research objects. They were randomly divided into control group and observation group, each containing 40 patients. Both groups of patients were subjected to anterior cervical discectomy and fusion internal fixation. However, the difference was that the control group was subjected to Rapid intravenous injection of 30 mg/kg methylprednisolone 30 min prior to spinal cord decompression, while the observation group was subjected to intravenous injection of both 30mg/kg methylprednisolone and 3000U/kg hemopoietin 30 min before spinal cord decompression. The neurological function of both groups of patients before treatment and 3 months after treatment was evaluated using JOA score (Japanese orthopeadic association score) and spinal cord function rating method (40-point rating method). ELISA was carried out to measure the level of S-100β, neurone specific enolase (NSE), IL-1β, IL-1Ra, IL-8 of two groups of patients; The life quality of patients in both groups 3 months after treatment was evaluated using WHOQOL-100.

Results: After 3 months of treatment, the JOA score and score of 40-point rating method for observation group was (18.33 ± 2.71) point and (39.12 ± 3.97) point, respectively, which were significantly higher than that (P=0.025,0.019) of control group; the level of S-100β and NSE in observation group was (0.08 ± 0.02)g/L and (9.51±0.45)g/L, respectively, which were significantly higher than values (P=0.031,0.022) of control group; the level of IL-1β and IL-8 in observation group was (21.73 ± 3.55)ng/L and (356.97 ± 32.26)ng/L, respectively, both of which were lower than the values (P=0.016,0.018) of control group; while the level of L-1Ra in observation was (21.63 ± 1.14)ng/L, which was higher than that (P=0.021)of control group; the WHOQOL-100 scores in physiology, psychology, independence, social relation, environment, spirit and overall life quality of observation group were all higher than that of control group, indicating the intergroup difference was of statistical significance (all P<0.001).

Conclusion: The combined therapy of hemopoietin and methylprednisolone achieved significant therapeutic effect in treatment of spinal cord ischemia-reperfusion injury. Moreover, this combined therapy had effective function in reducing S-100β and NSE, inhibiting IL-1β, increasing IL-8 and IL-1Ra, and thus realized protection of spinal cord nerve function and improved the life quality of patients. The combined therapy of hemopoietin and methylprednisolone is worth of being promoted in clinics.

Keywords

hemopoietin, methylprednisolone, cervical spondylotic myelopathy, spinal cord ischemia-reperfusion injury, IL 1β

Introduction

Cervical spondylotic myelopathy refers to nerve function deficit induced by spinal compression ischemia caused by degenerative pathological change of cervical vertebra, which is a typical clinical symptom [1]. The pathogenesis of cervical spondylotic myelopathy is degenerative pathological change of cervical vertebra. Due to the emergence of soft tissue outside the spinal cord and peripheral bone compression, the spinal cord nerve function is affected and location changing of anatomical structure is caused [2,3]. Cervical spondylotic myelopathy may lead to spinal cord blood supply disorder and venous reflux disorder, cause myelomalacia and myelonecrosis and result in abnormal spinal nerve function [4,5]. Although surgery can effective relieve spinal cord compression, it may also cause ischemia reperfusion injury in certain degree, thus affecting the recovery of nerve function after decompression [6,7]. Spinal cord ischemia reperfusion injury refers to non-improvement or even aggravation of nerve function after recovery of spinal cord blood supply. In some extremely serious cases, the spinal nerve cloud may suffer irreversible delayed neuronal death [8,9]. Methylprednisolone is an effective drug for treating spinal ischemia reperfusion. However, with the clinical use of methylprednisolone, it is gradually recognized that large dosage of methylprednisolone may cause complications such as gastrointestinal bleeding and osteonecrosis [10]. Hemopoietin determines the oxygenation state of tissues in large degree. The hemopoietin is highly expressed in central nervous system (CNS) cell, which exerts neurotropic effect, anti-neuron apoptosis, anti-oxidation and anti-inflammation functions via approach of autocrine and paracrine [11]. Currently, very few researches have been reported on the therapeutic effect of combined therapy of hemopoietin and methylprednisolone in treatment of spinal cord ischemia-reperfusion injury of patients with cervical spondylotic myelopathy. To this end, this study analyzes therapeutic effect of combined therapy of hemopoietin and methylprednisolone in treatment of spinal cord ischemia-reperfusion injury of patients with cervical spondylotic myelopathy and its influence to serum IL-1β, IL-1Ra and IL-8 level, which is expected to provide reference for spinal cord ischemia-reperfusion injury of patients with cervical spondylotic myelopathy.

Data and method

General data

80 patients who had been accepted for cervical spondylotic myelopathy in our hospital during March 2014 to September 2017 were selected as research objects.

Inclusion criteria

Patients who meet the diagnosis standard of cervical spondylotic myelopathy; under 75 years old in age; single section or two adjacent-section degeneration of lumbar intervertebral disc upon MRI test, significant signal indicating vascular myelopathies; no peripheral vascular diseases which affect upper limb function; no heart, liver, kidney and lung diseases; all selected patients enjoyed the right to know and accepted this study.

Exclusion criteria

Patients refuse to join in this test; having mental diseases; equal to or over 75 years old in age; having heart and kidney diseases; affect upper limb function by vascular disease. All 80 patients were randomly divided into control group and observation group, each containing 40. There was no significant difference in gender, age, body weight, height, disease course, site of lesion (single section/two adjacent-section) between two groups (P>0.05), as shown in Table 1.

Table 1. Comparison of general data between two groups

Therapeutic method

Both groups of patients were subjected to anterior cervical discectomy and fusion internal fixation for single-section or two adjacent-section intervertebral disk. The surgery was performed by the same group of surgeon for two groups. 30 min prior to spinal cord decompression, the control group was subjected to rapid intravenous injection of 30 mg/kg methylprednisolone (finished within 15 min), while the observation group was subjected to intravenous injection of both 30 mg/kg methylprednisolone and 3000U/kg hemopoietin (finished within 15 min). After surgery, each patient from both groups was orally administrated with 80 mg of methylprednisolone, once a day, for 2 consecutive weeks.

Observation indexes

Neurological functional status

The neurological function of both groups of patients before treatment and 3 months after treatment was evaluated using JOA score (Japanese orthopeadic association score) and spinal cord function rating method. The larger the score is, the better the neurological function status is.

Biochemical index

ELISA was carried out to measure the level of S-100β, neurone specific enolase (NSE), IL-1β, IL-1Ra, IL-8 of two groups of patients before treatment and 3 months after treatment; The ELISA kits were all purchased from Shanghai Runyu Biotechnology Co. Ltd.

Life quality

The life quality of patients in both groups 3 months after treatment was evaluated using WHOQOL-100. WHOQOL-100 includes 6 dimensions related to life quality, i.e. physiology, psychology, independence, social relation, environment and spirit. Furthermore, the WHOQOL-100 includes 24 items and each item includes 4 questions.

Plus 4 additional questions on overall health condition and overall life quality, there is totally 100 questions included in the WHOQOL-100. The higher the score in each dimension is, the better the life equality is.

Statistical treatment

SPSS 22.00 software was adopted for statistical analysis. The measurement data was expressed in the form of mean ± standard error (͞x ± s) and subjected to independent t-test; enumeration data was subjected to chi-square test, P<0.05 represents the different is of statistical significant.

Results

Comparison of neurological function score between two groups

Before treatment, there is no significant difference in JOA score and score of 40-point rating method between two groups (P>0.05); After 3 months of treatment, the JOA score and score of 40-point rating method for observation group was (18.33 ± 2.71)point and (39.12 ± 3.97) point, respectively, which were significantly higher than that (P=0.025, 0.019) of control group, as shown in Table 2.

Table 2. Comparison of neurological function score between two groups (Score, ͞x ± s)

Comparison of S-100βand NSE level between two groups

Before treatment, there was no significant difference in level of S-100 β and NSE between two groups (P=0.552,0.031); after 3 months of treatment, the level of S-100 β and NSE in observation group was (0.08±0.02) g/L and (9.51±0.45)g/L, respectively, which were significantly higher than values (P=0.031,0.022) of control group, as shown in Table 3.

Table 3. Comparison of S-100β and NSE level between two groups (g/L, ͞x ± s)

Comparison of level of IL-1β, IL-1Ra and IL-8 between two groups

Before treatment, there was no significant difference in level of IL-1β, IL-1Ra and IL-8 between two groups(P=0.252,0.377, 0.144); after 3 months of treatment, the level of IL-1β and IL-8 in observation group was (21.73±3.55) ng/L and(356.97±32.26) ng/L, respectively, both of which were lower than the values(P=0.016,0.018)of control group; while the level of L-1Ra in observation was (21.63±1.14) ng/L, which was higher than that (P=0.021)of control group, as shown in Table 4.

Table 4. Comparison of level of IL-1β, IL-1Ra and IL-8 between two groups (ng/L, ͞x ± s)

Comparison of life quality between two groups

After 3 months of treatment, the WHOQOL-100 scores in physiology, psychology, independence, social relation, environment, spirit and overall life quality of observation group were all higher than that of control group, indicating the intergroup difference was of statistical significance (all P<0.001), as shown in Table 5.

Table 5. Comparison of life quality between two groups after 3 months of treatment (Score, ͞x ± s)

Summary

After 3 months of treatment, the JOA score and score of 40-point rating method for observation group was (18.33 ± 2.71) point and (39.12 ± 3.97) point, respectively, which were significantly higher than that (P=0.025, 0.019) of control group; the level of S-100β and NSE in observation group was (0.08 ± 0.02)g/L and (9.51 ± 0.45)g/L, respectively, which were significantly higher than values (P=0.031, 0.022) of control group; the level of IL-1β and IL-8 in observation group was (21.73 ± 3.55)ng/L and (356.97 ± 32.26) ng/L, respectively, both of which were lower than the values (P=0.016, 0.018) of control group; while the level of L-1Ra in observation was(21.63 ± 1.14) ng/L, which was higher than that (P=0.021) of control group; the WHOQOL-100 scores in physiology, psychology, independence, social relation, environment, spirit and overall life quality of observation group were all higher than that of control group, indicating the intergroup difference was of statistical significance (all P<0.001).

Discussion

Cervical spondylotic myelopathy is a clinically common disease. Operative decompression has long been regarded as a dominant approach to treat such disease by relieving the compression applied on spinal cord and maintaining the stability of spine. However, since the compressed spine has already shown ichemic anoxic changes, a sudden increase of blood supply after operative decompression may cause ischemia reperfusion injury [12,13]. At present, there has been no specific therapy for spinal cord ischemia-reperfusion injury. Methylprednisolone is a synthetic glucocorticoid, which has therapeutic effect to spinal cord ischemia-reperfusion injury owe to its function of inhibiting lipid peroxidase and inflammatory response after trauma. This drug has strong anti-inflammatory action and is regarded as a standard therapy for acute spinal cord injury. Relevant literatures show [14] a large dosage of methylprednisolone may cause various untoward effects, which is unbeneficial for the improvement of neurological function. Researches show that [15] hemopoietin and its receptor are widely expressed in organs and tissues of human body, which have potential cytoprotection. Hemopoietin has neurotrophic activity, which can improve the brain tissue’s tolerance to ischemia-hypoxia and exerts neuroprotective effect via anti-cell apoptosis, anti-oxidation, anti-inflammation. This study showed that after 3 months of treatment the JOA scores and scores of 40-point rating method in observation group were both significant higher than that control group (P=0.025,0.019), indicating the combined therapy of hemopoietin and methylprednisolone can well promote the recovery of neurological function of patients with cervical spondylotic myelopathy.

Some researches show that [16] hemopoietin has similar function with platelet-derived growth factor (PDGF), both of which can improve the acitivity of antioxidant enzymes such as glutathion peroxidase; in addition, hemopoietin can inhibit the increase of thiobarbituric acid after ischemia-reperfusion injury, realizing the function of anti-brain lipid peroxidation. Serum neuron and astrocyte specific protein can effectively reflect the disease status of traumatic brain injury, cerebral infarction and spinal cord injury. The S-100β contained in hemopoietin is a type of ca-binding protein, which has certain correlation with some calcium ions exerting their own function by relying on cells. When the contents of S-100βand cerebrospinal fluid (CSF) are increased, the damage level of nervous centralis is proportion to the contents of S-100βand CSF [17]. NSE, as a potential marker in diagnosis of cerebral spinal cord injury, has attracted increasing attention. Previous researches [18] have proved that the increase of peripheral blood NSE level is positively correlated with the damage level of nervous centralis, while negatively related with prognosis. Some researches [19] show that serum NSE level can be regarded as a specific marker for acute stage of spinal cord injury. This research showed that after 3 months of treatment the level of S-100β and NSE in observation group was significantly higher than that of control group (P=0.031, 0.022), indicating the combined therapy of hemopoietin and methylprednisolone can effectively reduce the level of S-100βand NSE in serum, and thus relieving the spinal cord ischemia-reperfusion injury.

Research [20] shows that IL-1β is involved in the early development course of spinal cord ischemia reperfusion injury. The increase of expression of IL-1β after reperfusion injury is a main molecular basis accounting for blood spinal cord barrier lesion. Research shows [21] that IL-1Ra, IL-1R’s antagonist, can competitively combine with IL-1βreceptor to block biological effects of IL-1, thus defending the pathological damage caused by IL-1β and relieving ischemic injury. Positive expression or generation of IL-8 will not occur in normal spinal cord tissue, but only occur in the process of ischemia reperfusion injury (specifically, around endothelial cells), indicating IL-8 is mainly derived from endothelial cells. Hirose K et al. [22] studied the role of antithrombin in reducing ischemia reperfusion-induced inflammation of rats and relieving spinal cord injury and found that antithrombin could significantly inhibit the expression of IL-8. This research showed that after 3 months of treatment the level of IL-1β and IL-8 in observation group was lower than that in control group (P=0.016,0.018); while the level of IL-1Ra in observation group was higher than that in control group (P=0.021). This indicates the combined therapy of hemopoietin and methylprednisolone has advantages in inhibiting IL-1β and IL-8 and promoting IL-1Ra, and thus achieves better protection of spinal cord nerve function. Furthermore, this research shows that the combined therapy of hemopoietin and methylprednisolone can improve life quality of patients more significantly compared with single application of methylprednisolone.

Conclusion

The combined therapy of hemopoietin and methylprednisolone achieved significant therapeutic effect in treatment of spinal cord ischemia-reperfusion injury. Moreover, this combined therapy had effective function in reducing S-100β and NSE, inhibiting IL-1β, increasing IL-8 and IL-1Ra, and thus realized protection of spinal cord nerve function and improved the life quality of patients. The combined therapy of hemopoietin and methylprednisolone is worth of being promoted in clinics.

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