Clinical efficacy analysis of coenzyme Q10 combined with flunarizine in the treatment of migraine headache

 Abstract：Objective To investigate the clinical efficacy of coenzyme Q10 combined with flunarizine in the treatment of migraine. Methods 104 migraine patients admitted to the Third People's Hospital of Mianyang City, Sichuan Province, from January to June 2023 were selected for the study, and were divided into a control group and an observation group using the randomized numerical table method, with 52 cases in each group. The control group was treated with flunarizine, while the observation group was treated with coenzyme Q10 combined with flunarizine, and both groups were treated continuously for 6 months. Compare and analyze the clinical efficacy of the two groups and the occurrence of adverse reactions during the treatment period. Cerebral hemodynamic indexes (mean blood flow velocity of the posterior cerebral artery, mean blood flow velocity of the middle cerebral artery, mean blood flow velocity of the anterior cerebral artery), oxidative stress status (oxidized low-density lipoprotein (ox-LDL), argyrophilic esterase (ArE)), migraine symptoms (duration of migraine attacks, degree of migraine pain) and the incidence of adverse reactions during the treatment period were compared in the two groups before and after 6 months of treatment. Migraine symptoms (migraine attack duration, migraine pain, migraine attack frequency), and migraine pain were assessed using a numeric rating scale (NRS).

 

Results After 6 months of treatment, the total clinical effectiveness rate of patients in the observation group was higher than that of the control group, and the difference was statistically significant (P＜0.05). There was no statistically significant difference in the total incidence of adverse reactions between the two groups (P＞0.05). After 6 months of treatment, the average blood flow rate of middle cerebral artery, average blood flow rate of anterior cerebral artery, average blood flow rate of posterior cerebral artery, ox-LDL, frequency of migraine attacks and duration of migraine attacks of the patients in the two groups were lower or shorter than those in the control group, and the differences were statistically significant (P < 0.05). After 6 months of treatment, the PON-1 and ArE of both groups increased compared with the pre-treatment period, and the observation group was higher than the control group, and the differences were statistically significant (P<0.05). The differences in NRS scores between the two groups were not statistically significant when comparing patients before treatment and after 6 months of treatment (P＞0.05). The clinical efficacy of coenzyme Q10 combined with flunarizine in the treatment of migraine is remarkable, which can effectively improve the cerebral hemodynamics and oxidative stress status of the patients, and the safety is good.

 

Migraine is a common neurological disorder that can lead to severe disability, loss of productivity, and increased economic burden on families and society [1-2]. In China, the prevalence of primary migraine is as high as 23.8% [3]. In China, the prevalence of primary migraine is as high as 23.8% [3], and migraine occurs more often in young and middle-aged people, which can seriously affect the quality of life of patients [4].

 

At present, there is no cure for migraine, and the main goal of clinical treatment of migraine is to relieve migraine symptoms. It has been reported in the literature that flunarizine is a commonly used drug in the treatment of migraine, which can inhibit the inward flow of excess calcium ions into vascular smooth muscle cells, relieve cerebral vasospasm, improve cerebral blood flow kinetics, and thus effectively relieve migraine symptoms [5-6].

 

Overseas studies have pointed out that coenzyme Q10 is an antioxidant that can be used to improve the clinical characteristics of migraine [7]. However, there is still a lack of clinical evidence to support the efficacy of coenzyme Q10 in the treatment of migraine in China. Therefore, this study investigated the clinical efficacy of coenzyme Q10 combined with flunarizine in the treatment of migraine and its effect on cerebral hemodynamics, with the aim of providing an evidence-based basis for clinical application.

 

1 Objects and Methods

1.1 Subject of the study

A total of 104 migraine patients admitted to our hospital from January to June 2023 were selected for the study, and were divided into a control group and an observation group using a randomized numeric table method, with 52 cases in each group. Inclusion criteria:

(1) The diagnostic criteria for migraine are met [8];

② Age 18-80 years old; ③ Duration of the disease ≥ 1 year, frequency of migraine attacks > 2 times / month; ④ No contraindications to the drugs used in this study. Exclusion criteria: ① headache caused by other diseases; ② combined with liquid system diseases or digestive system diseases;

(iii) Combination of other craniocerebral diseases;

④ Combined mental illness;

⑤ Combined serious heart, lung, liver, and kidney dysfunction;

(vi) Combined infectious diseases.

 

The baseline data of gender, age, disease duration, body mass index, smoking history, alcohol consumption history and comorbidities of the two groups were comparable, with no statistically significant differences (P ＞ 0.05). The study was approved by the Medical Ethics Committee of the Third People's Hospital of Mianyang City, Sichuan Province [Approval No. 2022 (18)], and all patients were informed of the study and signed an informed consent form.

 

1.2 Methodology

Patients in the control group were treated with oral flunarizine, 5 mg/times, once /d. Patients in the observation group were treated with oral coenzyme Q10 combined with flunarizine, flunarizine 5 mg/times, once /d; coenzyme Q10 10 mg/times, three times /d. Patients in the two groups were treated continuously for 6 months, and were followed up once a week during the treatment period.  All patients completed the 6-month treatment, and there was no case dropout. All patients completed the treatment for 6 months, and no case was dropped. During the acute attack of migraine, NSAIDs were given according to the "Chinese Guidelines for the Diagnosis and Treatment of Migraine (2022 Edition)"[8] .

 

1.3 Observation indicators

1.3.1 Comparison and analysis of the clinical efficacy of the two groups after 6 months of treatment  

After 6 months of treatment, cure was defined as complete disappearance of migraine and other clinical symptoms, with no recurrence one month after stopping the drug; significant effect was defined as >75% reduction in the frequency of migraine attacks and >50% shortening of migraine duration; effective was defined as 50%～75% reduction in the frequency of migraine attacks and 25%～50% reduction in migraine duration; and ineffective was defined as <50% reduction in the frequency of migraine attacks and <25% reduction in the duration of migraine [8]. Ineffective is a reduction in the frequency of migraine attacks <50% and the duration of migraine <25% [8]. Total effective rate = (number of cured cases + number of cases with apparent effect + number of effective cases) / total number of cases × 100%.

 

1.3.2 Comparison and analysis of cerebral hemodynamic indicators before and after treatment in the two groups of patients  

The mean blood flow velocity of the posterior cerebral artery, middle cerebral artery, and anterior cerebral artery were measured by Doppler color ultrasonography before and after 6 months of treatment, respectively.

 

1.3.3 Comparison and analysis of oxidative stress before and after treatment in the two groups of patients  

Before and after 6 months of treatment, 5 ml of fasting venous blood was drawn from patients of both groups, and the levels of paraoxonase 1 (PON-1) and oxidized low density lipoprotein (ox-LDL) were measured by enzyme-linked immunosorbent assay; the levels of arylesterase (ArE) were measured by colorimetric analysis. The levels of arylesterase (ArE) were determined by colorimetric analysis.

 

1.3.4 Comparison and analysis of migraine symptoms before and after treatment of the two groups of patients  

The duration of migraine attacks, the degree of migraine pain, and the frequency of migraine attacks were recorded before and after 6 months of treatment, respectively. A numerical rating scale (NRS) was used to assess the migraine pain level of the two groups, and a higher NRS score indicated more severe pain [9].

 

1.3.5 Comparison and analysis of the occurrence of adverse reactions during the treatment of the two groups of patients  

Adverse effects during the treatment period were recorded, mainly including nausea, drowsiness, fatigue, gastrointestinal discomfort, and so on.

 

1.4 Data analysis and processing

SPSS 27.0 statistical software was used to analyze the data. Measurement data with normal distribution were expressed as "x ± s", and the t-test was used to compare the means between groups; count data were expressed as cases (%), and the χ2 test was used to compare the data between groups. p < 0.05 was regarded as statistically significant difference.

 

2 Results

2.1 Comparison of the clinical efficacy of the two groups of patients after 6 months of treatment

After 6 months of treatment, the total clinical effectiveness rate of the observation group was higher than that of the control group, and the difference was statistically significant (P < 0.05). The difference was statistically significant (P < 0.05).

 

2.2 Comparison of cerebral hemodynamic indexes before and after treatment in two groups of patients

Before treatment, there was no statistically significant difference between the mean blood flow velocities of the middle cerebral artery, anterior cerebral artery, and posterior cerebral artery in the two groups (P ＞ 0.05); after 6 months of treatment, the mean blood flow velocities of the middle cerebral artery, anterior cerebral artery, and posterior cerebral artery were lower than those in the control group, with a statistically significant difference (P ＜ 0.05). The differences were statistically significant (P < 0.05).

 

2.3 Comparison of oxidative stress status between the two groups of patients before and after treatment

Before treatment, there was no statistically significant difference in PON-1, ox-LDL and ArE between the two groups (P > 0.05). After 6 months of treatment, the PON-1 and ArE of both groups increased compared with those before treatment, and the observation group was higher than the control group, with statistically significant differences (P < 0.05); the ox-LDL of both groups decreased compared with those before treatment, and the observation group was lower than the control group, with statistically significant differences (P < 0.05). The difference was statistically significant (P < 0.05).

 

2.4 Comparison of migraine symptoms before and after treatment between the two groups of patients

Before treatment, there was no statistically significant difference in the duration of migraine attacks, NRS score, and frequency of migraine attacks between the two groups (P ＞ 0.05); after 6 months of treatment, the duration of migraine attacks, NRS score, and frequency of migraine attacks of the two groups were shorter or lower than before treatment, and the duration of migraine attacks and frequency of migraine attacks of the observation group were shorter or lower than that of the control group (P ＜ 0.05). In the observation group, the duration of migraine attacks and the frequency of migraine attacks were shorter or lower than those in the control group, and the differences were statistically significant (P < 0.05). The differences were statistically significant (P < 0.05).

 

2.5 Comparison of the occurrence of adverse reactions during treatment between the two groups of patients

There was no statistically significant difference in the total incidence of adverse reactions during treatment between the two groups (P ＞ 0.05). See Table 6.

Table 6 Comparison of the occurrence of adverse reactions during treatment in the two groups [cases (%)

 

3 Discussion

Flunarizine is the first-line drug recommended by the European Headache Consortium for the treatment of migraine, and can reduce the frequency of migraine attacks by more than 50% per month [10]. Previous studies in China have shown that flunarizine can significantly reduce the frequency of migraine attacks, alleviate the pain level, and effectively shorten the duration of migraine attacks [11]. Flunarizine has a strong lipid solubility and can easily cross the blood-brain barrier to act on the cerebral blood vessels, thus inhibiting cerebral vasospasm, and can effectively improve cerebral microcirculation and neuronal metabolism, thus relieving migraine symptoms [12-13]. However, the clinical efficacy of flunarizine alone is limited, and it is often necessary to combine it with other drugs [14].

 

According to the results of this study, after 6 months of treatment, the total clinical effectiveness rate of patients in the observation group was higher than that of the control group, and the duration of migraine attacks and the frequency of migraine attacks were shorter than or lower than those of the control group, with statistically significant differences. The difference is statistically significant, indicating that the combination of coenzyme Q10 and flunarizine in the treatment of migraine is clinically effective, and can effectively shorten the duration of migraine attacks and reduce the frequency of migraine attacks. Several studies have demonstrated that coenzyme Q10 can directly participate in the reaction of peroxyl radicals, synergize with vitamin E to enhance antioxidant capacity, and enhance human immune function, improve the oxidative state of the brain, and reduce the occurrence of abnormal energy metabolism, thus suppressing migraine attacks and shortening the duration of migraine attacks [15-16]. It has been reported that coenzyme Q10 can effectively reduce the frequency and duration of migraine attacks [17]. A meta-analysis of 371 adult migraine patients showed that coenzyme Q10 could significantly reduce the duration and frequency of migraine attacks [18].

 

The results of this study showed that after 6 months of treatment, the mean blood flow velocity of middle cerebral artery, the mean blood flow velocity of anterior cerebral artery, the mean blood flow velocity of posterior cerebral artery, and ox-LDL of patients in both groups were lower than or shorter than that of the control group, and the mean blood flow velocity of PON-1, and ArE of patients in both groups were higher than those of the control group, with the difference being statistically significant.

 

Coenzyme Q10 combined with flunarizine can effectively improve cerebral hemodynamics and oxidative stress in migraine patients. Overseas studies have shown that supplementation of coenzyme Q10 can up-regulate the expression of antioxidant defense system enzymes and inhibit oxidative stress [19].

 

Studies in China have also shown that coenzyme Q10 can effectively inhibit oxidative stress in the treatment of rheumatoid arthritis and hypertension combined with arrhythmia [20-21]. The results of this study showed that there was no statistically significant difference in the total incidence of adverse reactions between the two groups. This suggests that the safety of coenzyme Q10 combined with flunarizine in the treatment of migraine is better.

 

In conclusion, the clinical efficacy of coenzyme Q10 combined with flunarizine in the treatment of migraine headache is remarkable, and it can effectively improve the cerebral hemodynamics and oxygenation stress status of the patients, and the safety is good. However, the sample size of this study is small and the follow-up period is short, so the long-term efficacy of coenzyme Q10 combined with flunarizine in the treatment of migraine has not been clarified, and needs to be further investigated in the future.

 

References:

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[6] RASHID S M U, SUMARIA S, KOOHI N, et al. Patient experience offlunarizine for vestibular migraine: single center observational study[J]. Brain Sci, 2022, 12(4): 415.

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[10]DELIGIANNI C I, SACCO S, EKIZOGLU E, et al. European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 2: Flunarizine[J]. J Headache Pain, 2023, 24(1): 128.

[11] CHEN Jie, TIAN Huijuan, ZHANG Wei, et al. Effects of Chuanxiong Qingcheng Granules combined with flunarizine on cranial hemodynamics and levels of ET-1, 5-HT and CGRP in migraine patients[J]. Guizhou Medicine, 2022, 46(2): 302-303.

[12]LI W, LIU R T, LIU W D, et al. The effect of topiramate versus flunarizine on the non-headache symptoms of migraine[J]. Int J Neurosci, 2023, 133(1): 19-25.

[13]ZHU J L, CHEN J H, ZHANG K X. Clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine comorbidity of depression and anxiety disorder[J]. Brain Behav, 2022, 12(8): e2689.

[14] LI Yuyu, MA Bo, XU Li. Study on the effect of heptaphylloside sodium tablets combined with flunarizine hydrochloride in the treatment of migraine[J]. Chinese Family Medicine, 2022, 20(7): 1102-1105.

[15] PAROHAN M, SARRAF P, JAVANBAKHT M H, et al. Effect of coenzyme Q10 supplementation on clinical features of migraine: a systematic review and dose- response meta-analysis of randomized controlled trials[J]. Nutr Neurosci, 2020, 23(11): 868-875.

[16]MANTLE D, HEATON R A, HARGREAVES I P. Coenzyme Q10, ageing and the nervous system: an overview[J]. Antioxidants (Basel), 2021, 11(1): 2.

[17] LUO Guochen, ZHAO Ruichao.  Effects of oral coenzyme Q10 on inflammatory factors and headache symptoms in migraine patients[J]. Medical Theory and Practice, 2021, 34(3): 410-412.

[18]SAZALI S, BADRIN S, NORHAYATI M N, et al. Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine-a meta-analysis[J]. BMJ Open, 2021, 11(1): e039358.

[19]AKBARI A, MOBINI G R, AGAH S, et al. Coenzyme Q10 supplementation and oxidative stress parameters: a systematic review and meta-analysis of clinical trials[J]. trials[J]. Eur J Clin Pharmacol, 2020, 76(11): 1483-1499.

[20] Zhu Keda, Wang Rinjie, Liu Fengyun, et al. Effects of coenzyme Q10 on the levels of pro-inflammatory cytokines and oxidative stress in patients with rheumatoid arthritis[J] . Guangxi Medicine, 2020, 42(4): 417-420, 460.

[21] LIU Cui, GAO Xiang. Efficacy and mechanism of action of coenzyme Q10 in the adjuvant treatment of hypertension combined with arrhythmia in the elderly[J]. International Journal of Geriatrics, 2023, 44(2): 218-222.

 

Study on COQ 10 for Fatigue in Rats Simulating Acute Plateau Environment

 In recent years, with the development of the west, military operations, tourism and vacation activities, people's acute exposure to high altitude has become more and more frequent. Relevant studies have shown that labor efficiency at altitudes of 3500 and 4500 m decreases by 12.61% and 18.78%, respectively, compared to plains [1]. It takes days or even weeks for the body to adapt to the altitude environment, and serious complications are likely to occur in the early days (within a few days) of acute altitude exposure [2]. Reduced fatigue and pathophysiologic changes in the body after rapid entry to the plateau affect the normal work and life of the personnel and limit the smooth implementation of plateau activities.

 

Acute exposure to high altitude aggravates hypoxemia, which results in insufficient oxygen supply and restricted movement; at the same time, the metabolic reflexes of the respiratory muscles regulate blood redistribution, resulting in a decrease in blood supply to the muscles [3 - 4]. The decrease of oxygen partial pressure in the nervous system, the decrease of neurotransmitter conversion and synaptic transmission, the weakening of ion channels and ion pumps, and the abnormality of neuromuscular junction conduction [5-6], all these pathophysiological changes can aggravate the fatigue of operation.

 

Mitochondrial respiration produces ATP and consumes O2, which is accompanied by the production and removal of reactive oxide species (ROS). As the intensity of work increases, ROS production increases and clearance decreases, and ROS are mainly oxidized by the Na+-K+ pump, resulting in an imbalance of Na+ and K+ concentrations in and out of the skeletal muscle cell, affecting the excitability of the cell membrane, and inhibiting the release of Ca2+ from the sarcoplasmic reticulum and the sensitivity of myofibrils to Ca2+, thus leading to muscle fatigue [7]. In addition, ROS activate class IV muscle afferent nerve fibers and directly inhibit motor neurons [8].

 

 It has been reported in the literature that an increase in ROS can lead to fatigue, and that pretreatment of isolated rat tibialis anterior muscle with superoxide dismutase (SOD) injections reduced the frequency of afferent nerve excitation, which in turn significantly ameliorated fatigue. The dysfunction of mitochondrial oxidative phosphorylation increases the production of ROS, which further oxidizes and destroys the mitochondrial membrane, electron transport system and tricarboxylic enzyme, and further inhibits mitochondrial oxidative phosphorylation, thus forming a vicious cycle [9-11]. Within 72 h after acute altitude entry, the body's antioxidant capacity was significantly weakened, oxidative stress increased significantly, and lipid peroxidation level peaked at 48 h [12]. The oxidative stress at the early stage of plateau entry aggravates the fatigue of the organism and affects its ability to act.

 

Coenzyme Q10 (CoQ10) is found in a wide range of tissues and organs in the human body, with high levels in central, renal and hepatic tissues where metabolism is high, and in organelles, mainly in Golgi vesicles, mitochondrial plasma membranes and lysosomes [13]. CoQ10 is a mitochondria-targeting small molecule that promotes ATP production by participating in the electron transport chain in mitochondria. At the same time, CoQ10 is an important fat-soluble antioxidant that protects cell membranes, mitochondria and other organelles (e.g., Golgi, lysosomes, endoplasmic reticulum, and peroxisomes) from free radical-induced oxidative stress.

 

In addition to its direct role as an antioxidant, CoQ10 is also involved in the regeneration of the antioxidants vitamin C and vitamin E. CoQ10 is approved by the Food and Drug Administration (FDA) for use as a dietary supplement, and has been well tolerated, but its effects on the ability to operate in an acute plateau and on fatigue have not been studied in depth. In this study, we evaluated the anti-fatigue effect of CoQ10 in a rat model of acute plateau exposure and explored its possible mechanisms.

 

1 Materials and Methods

1.1 Animals

SPF grade male Wistar rats, body weight 200~230 g, Beijing Witong Lihua Co., Ltd, Production License No.: SCXK (Beijing) 2016-0011. The feeding environment was 40%~60% humidity, 23-27℃, 12-hour day/night cycle (light time 8:00~20:00), free intake of food and water, and the feeding process was in accordance with the guidelines of the Ethics Committee for Laboratory Animals of the Military Medical Research Institute of the Military Academy of Sciences. Ethical approval number: IACUC-DWZX-2020-778.

 

1.2 Drugs, Reagents and Major Instruments

CoQ10, sodium carboxymethyl cellulose (CMC-Na), and 4% tissue cell fixative, Beijing Solepol Technology Co. Malondialdehyde (MDA) kit and total superoxide dismutase (T-SOD) kit, Nanjing Jianjian Bioengineering Research Institute, Nanjing, China; TUNEL kit, Rexroth; DAB developer, Wuhan Xavier Biotechnology Co. 96-well enzyme labeling plate, Corning, USA; OmegaA15-3677 fully automated enzyme labeling instrument, BMGLABTECH, Germany; TDL-5M centrifuge, Sichuan, China; TDL-5M centrifuge, Sichuan, China; TDL-5M centrifuge, Sichuan, China; TDL-5M centrifuge, Sichuan, China. -Ltd., Guizhou Fenglei Aviation Ordnance Co., Ltd; Vit-ro-950 blood gas analyzer, Johnson & Johnson, USA; Vert.A1 optical microscope, Zeiss, Germany; rat swimming pool, manufactured by the laboratory.

 

1.3 Establishment and Grouping of the Rat Acute Plateau Model

Wistar rats were divided into normal pressure and normoxia (NN) group, hypobaric and hypoxia (HH) group and HH + CoQ10 group, with 12 rats in each group. The HH + CoQ10 group received CoQ10 30 mg kg-1 (prepared as a suspension with 0.5% CMC-Na) as a single daily ig-administration for 6 days, and the remaining 2 groups were given an equal volume of solvent in the same manner. After 4 d of administration, the rats in the HH and HH +CoQ10 groups were transferred to a low-pressure oxygen chamber and ascended to a simulated altitude of 6000 m at a speed of 5 m-s-1 for 2 d. The rats in the NN group were kept under NN conditions.

 

1.4 Swimming Exhaustion in Rats

One hour after the last dose, 6 rats in each group were randomly selected for the swimming exhaustion test. Before the experiment, the rats were weighed and a lead block weighing 8% of their body weight was attached to their tails. The rats were placed in a water tank with a depth of 30 cm and a water temperature of 27~30℃ for the exhaustion swimming test. The rats were judged to be exhausted when they were submerged underwater for ≥10 s. The time of exhaustion was recorded. The exhaustion time was recorded.

 

1.5 Preparation of rat blood samples, blood gas analysis and assay of serum MDA content and T-SOD activity

One hour after the last dose, the remaining 6 rats in each group were anesthetized and placed in the supine position, and blood was collected from the abdominal aorta with a heparinized 1 mL syringe. Aortic blood was partially sealed, and arterial blood pH, arterial carbon dioxide pressure (PaCO2), arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), and arterial oxygen saturation (SaO2) were analyzed by a blood gas analyzer within 10 min. arterial oxygen saturation (SaO2), and alkali residual (BE).    Arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), and alkali residual (BE), arterial bicarbonate (HCO3-), serum calcium ion (Ca2+), and arterial lactate (Lac) levels were measured. A portion of aortic blood was centrifuged in a centrifuge tube at 450×g for 10 min at 4°C. The serum was extracted, and MDA and T-SOD activity were measured according to the instructions of the kit.

 

1.6 HE staining to observe the histopathological changes in heart, kidney, lung and brain tissues of rats

After blood sampling and execution, the apical tissues of heart, left kidney, left lung and left cerebral hemisphere of rats were fixed with 4% paraformaldehyde, dehydrated with ethanol gradient, transparent with xylene, embedded in paraffin and made into 5 μm paraffin sections. After HE staining, dehydrated and sealed, the pathological changes of heart, lung, kidney and brain tissues were observed under microscope.

 

1.7 TUNEL Assay for Apoptosis in Rat Heart, Liver, Kidney, Lung and Brain Tissues

Prepare heart, kidney, lung and brain tissue sections, and subject them to ethanol gradient dehydration, antigen repair and cell membrane rupture treatment, according to the instructions of the kit. After staining, sealing and microscopic observation, cells with brownish-yellow particles in the nucleus are positive cells, i.e. apoptotic cells. 

 

1.8 Statistical Analysis

The experimental data were expressed as x±s and analyzed statistically using SPSS18.0 software. The results of HH swim exhaustion time, HCO3-, BE, Lac and Ca2+ in NN did not conform to normal distribution, and the Mann-Whitney rank sum test was used for comparison between groups. The other results were normally distributed, and t-tests with independent samples were used. p<0.05 was considered statistically significant.

 

2 Results

2.1 Effect of CoQ10 on the duration of swimming exhaustion in a rat model of simulated acute altitude progression

 

After 48 h of simulated rapid advancement to 6000 m plateau, the swimming exhaustion time of rats in the HH group was significantly shorter than that of rats in the NN group (P<0.01), and the swimming exhaustion time of rats in the HH+CoQ10 group was significantly longer than that of rats in the HH group (P<0.05) (Figure 1). This suggests that CoQ10 has a certain anti-fatigue effect.

 

Fig. 1 Effect of coenzyme Q10 (CoQ10) on exhaus⁃ tive swimming time in rushing-into-plateau model rats. Wistar rats were randomly divided into three Wistar rats were randomly divided into three groups: normal pressure and normoxia [NN, vehicle (0.5% CMC-Na)] group, hypo⁃ baric and hypoxia (HH, vehicle) group, and HH +CoQ10 group (CoQ10 30 mg-kg-1). All rats except those in NN group were rushed into a high altitude of 6000 m 4 d after preventive administration . Vehicle and CoQ10 were administrated for another 2 d. x± s, n=6. **P<0 .01, compared with NN group; # P<0 .05 , compared with HH group.

 

2.2 Effect of CoQ10 on Blood Gas Indexes of Rats in the Acute Plateau Model

As shown in Table 1, after 48 h of simulated rapid advancement to a plateau of 6000 m, arterial blood pH, PaO2, SaO2 and HCO3- levels in the HH group were significantly lower (P<0.01), and PaCO2, BE, Ca2+ and Lac levels were significantly higher (P<0.01) compared with those in the NN group. Compared with rats in the HH group, arterial blood pH was significantly increased (P<0.05), and PaCO2, Ca2+ and Lac levels were significantly decreased (P<0.05) in the HH + CoQ10 group. It was suggested that CoQ10 could improve acidosis and hyperCO2emia and reduce the serum Lac level in rats exposed to the plateau environment.

  

Tab. 1 Effect of CoQ10 on arterial blood gas analysis of rushing-into-plateau model rats

 

Parameter	NN	HH	HH+CoQ10
pH	7.42±0.11	6.88±0.16**	7. 10±0.15#
PaCO2 /mmHg	38±16	64±7**	40±23#
PaO2 /mmHg	107±11	43±19**	58±28
SaO2 /%	95±3	23±16**	46±28
BE/mmol-L-1	-0.7±9.8	-18.1±4.3**	-18.1±3.1
HCO3- /mmol-L-1	24.3±7.1	10. 1±1.9**	11.2±1.8
Ca2+/mmol-L-1	1.29±0.18	1.54±0.06**	1.33±0.21#
Lac/mmol-L-1	2.8±3.5	12.8±2.4**	9.5±2.0#

See Fig. 1 for the rat treatment. PaCO2 : arterial carbon dioxide pressure; PaO2 : arterial oxygen partial pressure; SaO2 : arterial oxygen saturation; BE. alkali residual; HCO : arterial bicarbonate; Ca : serum calcium ion; Lac: alkali residual; HCO3- : arterial bicarbonate; Ca2+ : serum calcium ion; Lac: arterial lactate. 1 mmHg=0.133 kPa. x±s, n=6. **P<0.01, compared with NN group;# P<0.05, compared with HH group.

 

2.3 Effects of CoQ10 on the histopathological structure of heart, lung, kidney and brain tissues in rats in the acute plateau model

HE staining results (Figure 2) showed that in the NN group, the cardiomyocytes had clear boundaries, clear nuclei, and no obvious cytoplasmic degeneration and necrosis; the renal tubules and glomeruli had normal structure; the alveolar walls were thin, the alveolar septa were clear, and the vesicles were obvious; neurons in the brain tissue were of normal morphology and size, and the nuclei were large and obvious. In HH+CoQ10 group rats, myocardial, renal, lung and brain tissues showed similar pathological changes to those in HH group rats, but to a lesser extent. It is suggested that CoQ10 can improve pulmonary edema and cerebral edema, and reduce the swelling of renal tubular epithelial cells in rats simulating acute plateau environment.

 

2.4 Effect of CoQ10 on apoptosis in heart, lung, kidney and brain tissues of rats in the acute plateau model

TUNEL staining showed that the apoptosis rates of heart, lung and brain cells in the NN, HH and HH+CoQ10 groups (data omitted) were not significantly altered (Figure 3). The apoptosis rate of renal tubular epithelial cells in the HH group was significantly increased compared with that in the NN group (P<0.01), and the apoptosis rate of renal tubular epithelial cells in the HH+CoQ10 group was significantly decreased compared with that in the HH group (P<0.01) (Figure 4). It was suggested that CoQ10 could improve the apoptosis of renal tubular epithelial cells in rats exposed to the acute plateau environment.

 

2.5 Effect of CoQ10 on serum T-SOD activity and MDA content in the acute plateau model rats

Compared with rats in the NN group, serum T-SOD activity was significantly lower (P<0.01) and MDA content was significantly higher (P<0.01) in the HH group; compared with rats in the HH group, serum T-SOD activity was significantly higher (P<0.05) and MDA content was significantly lower (P<0.05) in the HH+CoQ10 group (Figure 5). It was suggested that CoQ10 could improve the level of serum oxidative stress in rats exposed to acute plateau environment.

 

3 Discussion

The existing simulated plateau model and the altitude of human life in high altitude areas of China is more than 4000 m. According to the literature, exposure to altitude of 5000-6000 m for 24-72 h can induce tissue pathological changes in acute plateau models [15]. According to the literature, exposure to altitude of 5000-6000 m for 24-72 h can induce histopathological changes in animals with acute plateau [15]. Therefore, in the present study, we used an altitude of 6000 m for 48 h and a low-pressure oxygen chamber to simulate the plateau environment to establish a rat model of acute plateauing, which can reach the altitude quickly and effectively reduce the experimental bias caused by the habituation of the animals and other factors during transportation to the plateau.

 

The results of this study showed that compared with the rats in the HH group, the preventive administration of CoQ10 significantly prolonged the time of swimming exhaustion, alleviated acidosis and high CO2emia, and significantly improved the histopathological damage of the brain, lungs and kidneys as well as the serum oxidative stress, which suggests that CoQ10 can effectively alleviate fatigue at the early stage of the plateau, improve the pathological damage of the lungs, brain, kidneys and other important organs, alleviate the oxidative damage, and maintain the health of the body. It can also reduce the oxidative damage of tissues and maintain the health of the body.

 

CoQ10 has been widely used as a nutritional supplement, and 300 mg-d-1 has been generally recommended for human use, and no toxic effects have been observed [16]. In the present study, we aimed to investigate the effects of CoQ10, which is commonly used in human dosage, on simulated plateau rats. 30 mg kg-1 was administered to rats in a single daily dose according to the human-rat dosage conversion (body surface area conversion method) [17], which is one of the conventional dosages of CoQ10 in CoQ10 studies [18-19].

 

In the present study, we found that the exercise capacity of rats decreased significantly after 48 h of exposure to simulated 6000 m plateau, and the administration of CoQ10 significantly improved the physical performance of rats. At the same time, rats in the HH group showed typical pathological changes of pulmonary and cerebral edema, such as thickening of the alveolar wall, proliferation of the alveolar epithelium, edema of cerebral neuronal cells, and nuclear consolidation, which were ameliorated by the administration of CoQ10.

 

 It has been reported in the literature that CoQ10 can improve lipopolysaccharide-induced lung injury through its anti-inflammatory effect, and the administration of CoQ10 reduced serum C-reactive protein levels by 44.58%, alkaline phosphatase activity by 37.38%, and lactate dehydrogenase levels by 48.6%, resulting in a significant improvement in the pathologic damage of the lung tissue [20]. In another study on anesthesia and non-transplantation mild lung injury, it was also found that CoQ10 could play a role in lung protection by reducing the expression of tumor necrosis factor α [21]. These reports are consistent with the results of the present study.

 

Recent studies have shown that the kidney plays an important role in adaptation to the environment and plateau disease syndrome (acute high altitude sickness, high altitude cerebral edema and high altitude pulmonary edema) by regulating body fluids, electrolytes and acid-base balance, and renal injury occurs mostly in 2-4 d after acute altitude entry [12, 22-23]. In the present study, we found that the renal tubular epithelial cells in the HH group showed obvious edema and apoptosis, and the rate of apoptosis was significantly higher than that in the NN and CoQ10 groups, which indicated that CoQ10 had a certain protective effect on the early stage of renal tubular injury in the plateau-accelerated rats.

 

The results of this study showed that the serum MDA level was significantly increased and the T-SOD activity was significantly decreased in the HH group, while the administration of CoQ10 significantly decreased the serum MDA and increased the level of T-SOD. MDA is a peroxide formed by the attack of oxygen radicals on the polyunsaturated fatty acids in the biofilm, which triggers lipid peroxidation, and the level of MDA reflects the damage caused by oxidative stress in the organism [24]. T-SOD plays an important role in the redox balance of the organism, scavenging superoxide anion radicals (-O-2) and protecting cells from damage, and its activity can indirectly reflect the ability of the organism to scavenge oxygen radicals [24].

 

Goldfarb et al. [25] and Thirupathi et al. [26] found that antioxidant supplementation could reduce muscle damage, relieve fatigue, and improve work capacity. Other studies have reported that taurine supplementation can improve exercise capacity and reduce muscle damage [27-28]. However, some studies have reported that a large amount of exogenous antioxidant supplementation may interfere with the signaling pathway of the oxidative reduction response of myocytes, affecting their oxygen radical scavenging ability, and the advantages of CoQ10 as an endogenous antioxidant are more obvious [29].

 

In conclusion, CoQ10 can correct the acidosis and hyperCO2emia caused by pulmonary edema, improve the pathological damage of heart, lung, kidney and brain tissues, inhibit oxidative stress, and improve the anti-fatigue ability of the organism in the acute plateau environment.

 

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