Skip to main content
Erschienen in: BMC Musculoskeletal Disorders 1/2020

Open Access 01.12.2020 | Research article

Bilobalide protects against ischemia/reperfusion-induced oxidative stress and inflammatory responses via the MAPK/NF-κB pathways in rats

verfasst von: Ying Li, Jiliang Jiang, Liangcheng Tong, Tingting Gao, Lei Bai, Qing Xue, Jianxin Xing, Qin Wang, Haoran Lyu, Min Cai, Zhongyang Sun

Erschienen in: BMC Musculoskeletal Disorders | Ausgabe 1/2020

Abstract

Background

Clinically, skeletal muscle ischemia/reperfusion injury is a life-threatening syndrome that is often caused by skeletal muscle damage and is characterized by oxidative stress and inflammatory responses. Bilobalide has been found to have antioxidative and anti-inflammatory effects. However, it is unclear whether bilobalide can protect skeletal muscle from ischemia/reperfusion injury.

Methods

The effects of bilobalide on ischemia/reperfusion-injured skeletal muscle were investigated by performing hematoxylin and eosin staining and assessing the wet weight/dry weight ratio of muscle tissue. Then, we measured lipid peroxidation, antioxidant activity and inflammatory cytokine levels. Moreover, Western blotting was conducted to examine the protein levels of MAPK/NF-κB pathway members.

Results

Bilobalide treatment could protected hind limb skeletal muscle from ischemia/reperfusion injury by alleviating oxidative stress and inflammatory responses via the MAPK/NF-κB pathways.

Conclusions

Bilobalide may be a promising drug for I/R-injured muscle tissue. However, the specific mechanisms for the protective effects still need further study.
Hinweise
The original version of this article was revised: the authors noticed that the article title has a garbled code.
A correction to this article is available online at https://​doi.​org/​10.​1186/​s12891-020-03607-5.

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s12891-020-03479-9.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
CAT
Catalase
GSH-Px
Glutathione peroxidase
H&E
Hematoxylin and eosin
IL-1β
Interleukin 1 beta
IL-6
Interleukin 6
I/R
Ischemia/reperfusion
MAPK
Mitogen-activated protein kinase
MDA
Malondialdehyde
MPO
Myeloperoxidase
NADPH
Nicotinamide adenine dinucleotide phosphate
NF-κB
Nuclear factor kappa-B
ROS
Reactive oxygen species
SOD
Superoxide dismutase
TNF-α
Tumor necrosis factor alpha

Background

Limb ischemia/reperfusion (I/R) injury is a life-threatening syndrome that is often caused by trauma, primary thrombosis, arterial embolism, limb or flap reattachment, artery transplantation, prolonged tourniquet application, and abdominal compartment syndrome [1]. Mild I/R injury can lead to skeletal muscle fibrosis, persistent damage and necrosis, which can affect limb function; in severe cases, patients may require amputation. Patients with severe limb I/R injury can develop multiple organ dysfunction syndromes that threaten their lives [2].
Though the mechanisms of skeletal muscle I/R injury are diverse, a growing body of evidence has proved that oxidative stress and inflammatory responses have important roles in the progress of skeletal muscle I/R injury [3, 4]. Overproduction of reactive oxygen species (ROS) has been observed in I/R-injured organs. Excessive production of ROS can initiate lipid peroxidation, inactivate antioxidative stress-related proteins, and aggravate I/R injury [4]. Thus, injury can stimulate lipid peroxidation of biological membranes. Notably, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and the levels of F2-isoprostanes and malondialdehyde (MDA) are often used as indicators of oxidative stress [36]. Various defense mechanisms are induced by ROS-induced injury, and the levels of antioxidants such as catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) are often used as indicators of oxidative stress [3, 7]. In addition, ROS-induced injury can promote the formation and release of many inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β) [49]. Under oxidative stress or inflammatory conditions, the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways can be activated [10]. Many I/R injury models have been reported to elicit activation of the p38, JNK, ERK1/2 and p65 pathways [8, 9]. Specifically, it has been reported that activation of p38 and ERK1/2 is involved in renal I/R injury [11]. Furthermore, blockade of P38 α and β may protect the lungs from acute I/R injury by reducing the expression of IL-1β [12]. Moreover, 6-gingerol exerts protective effects against I/R-induced intestinal mucosal injury by inhibiting the formation of ROS and the activation of p38 and NF-κB [13]. It has also been reported that gypenoside protects cardiomyocytes against I/R injury through inhibition of MAPK pathway signaling and NF-κB p65 translocation into nuclei [14].
Based on this information, inhibition of the production and release of ROS and inflammatory cytokines is considered one of the strategies for addressing limb I/R injury. Ginkgo biloba can alleviate injury associated with stroke or myocardial infarction through its powerful antioxidant and anti-inflammatory properties [15, 16]. Bilobalide is one of the major pharmacological components of Ginkgo biloba. It has been reported that bilobalide can protect neurons and endothelial cells from oxidative and inflammatory stress injury [15, 16]. However, at present, little is known about whether bilobalide can protect skeletal muscle from I/R injury. In this study, we hypothesized that bilobalide could alleviate skeletal muscle damage caused by I/R injury by relieving oxidative stress and systemic inflammatory responses. To test this hypothesis, we examined the effects of bilobalide on skeletal muscle using methods including hematoxylin and eosin (H&E) staining and assessment of the wet weight/dry weight ratio of muscle tissue. Then, we measured lipid peroxidation, antioxidant activity, and inflammatory cytokine levels using test kits. Finally, we examined the activation of members of the MAPK and p65 NF- κB pathways via Western blotting.

Methods

Animals and ethics statement

For this study, male Sprague-Dawley rats aged 6–8 weeks were obtained from the Jiangsu Province Laboratory Animal Center. All rats were sacrificed by cervical dislocation after the experiment. All experimental procedures were approved by the Ethics Committee for Animal Use of Anhui Medical University.

Rat model of femoral artery I/R

All rats were treated with 3 h of ischemia and 24 h of reperfusion. The femoral artery was found, and the blood supply was interrupted with an atraumatic microvascular clamp. To completely block the blood flow of the hind limbs, a band was fitted around the right greater trochanter after limb exsanguination. The blood supply was restored after 3 h (to stop the ischemic conditions) by removing the clamp and band. Blood was allowed to reperfuse the area for an additional 24 h before sampling [8, 9].

Experimental groups and drug treatment

Thirty-two rats were randomly assigned to the following four groups of 8 rats each: (1) the sham group, (2) the I/R group (3) the I/R + bilobalide-low (4 mg/kg) group, and (4) the I/R + bilobalide-high group (12 mg/kg).
Bilobalide was purchased from Shanghai Winherb Medical Development. In the sham group, the femoral artery was only isolated for 3 h, and the rats were injected with saline intraperitoneally before reperfusion. In the I/R group, the femoral artery was blocked for 3 h, and the rats were injected with saline intraperitoneally before reperfusion. In the I/R + bilobalide-low group, the femoral artery was blocked for 3 h, and the rats were intraperitoneally injected with saline containing 4 mg/kg bilobalide before reperfusion. In the I/R + bilobalide-high group, the femoral artery was blocked for 3 h, and the rats were intraperitoneally injected with saline containing 12 mg/kg bilobalide before reperfusion [7]. In most studies, 3–15 mg/kg bilobalide has been used as the effective concentration for experiments [1719]. Therefore, we chose 4 mg/kg and 12 mg/kg in this study to further explore the effects of bilobalide on skeletal muscle I/R injury. Notably, 12 mg/kg bilobalide had no effects on the skeletal muscles of healthy rats (Supplementary Figure 1).

Morphometric analysis

Gastrocnemius muscle tissues were embedded in paraffin and cut into 3–5 μm-thick sections. For histological quantification of hind limb muscle fiber injury, five random fields were evaluated for damage. Uninjured fibers were characterized as having well-defined borders and morphologic uniformity without holes or breaks, while injured fibers exhibited broken, fragmented fiber morphologies. Blinded observers scored the morphological impairment according to previously published methods based on muscle fiber disorganization and degeneration and on inflammatory cell infiltration. A score of 0 indicated no damage, 1 indicated mild damage, 2 indicated moderate damage, 3 indicated severe damage, and 4 indicated very severe damage. The damage score was calculated as the sum of each of the parameters [4, 8, 20].

Wet weight/dry weight ratio of muscle tissue

The tibialis anterior muscle of each rat was weighed immediately after it was taken from the right hind limb (wet weight). The samples were dehydrated and weighed again (dry weight). The level of tissue edema was evaluated by the wet/dry ratio as follows: wet/dry ratio = (wet weight/dry weight) × 100% [4, 8].

Measurement of lipid peroxidation and antioxidant activity

NADPH oxidase activity and F2-isoprostane levels in muscles were determined as described previously [5, 6]. MDA concentrations were assessed by using a commercial kit (A003–1-2, Nanjing Jiancheng Biotechnology Institute, China). The activity levels of SOD (A001–3-2), GSH-Px (A005–1-2) and CAT (A007–1-1) in muscle homogenate were measured using kits (Nanjing Jiancheng Biotechnology Institute, China) according to the manufacturer’s instructions [4].

Measurement of myeloperoxidase (MPO) activity and inflammatory cytokine levels

An MPO Detection Kit (A044–1-1, Nanjing Jiancheng Biotechnology Institute, China) was used to determine the activity of MPO by measuring the H2O2-dependent oxidation of 3,3′-dimethoxybenzidine in order to assess neutrophil infiltration.
The levels of TNF-α (H052), IL-6 (H007) and IL-1β (H002) in serum were measured with ELISA kits (Nanjing Jiancheng Biotechnology Institute, China) according to the manufacturer’s instructions [4, 8].

Western blotting

Muscle tissues were lysed with RIPA buffer (Thermo Fisher Scientific, USA). Protein samples were boiled with loading buffer and then separated by SDS/PAGE prior to being transferred to a nitrocellulose membrane. The nitrocellulose membrane was incubated for 5 h at room temperature with primary antibodies. The primary antibodies included anti-P-P38 (ab4822; 1:1000 dilution; Abcam, USA), anti-P38 (ab31828; 1:1000 dilution; Abcam, USA), anti-P-ERK1/2 (ab223500; 1:400 dilution; Abcam, USA), anti-ERK1/2 (ab17942; 1:1000 dilution; Abcam, USA), anti-P-JNK (ab227061; 1:1000 dilution; Abcam, USA), anti-JNK (ab225572; 1:1000 dilution; Abcam, USA), anti-P65 (ab16502; 1:1000 dilution; Abcam, USA) and anti-β-actin (ab8227; 1:2000 dilution; Abcam, USA). The blots were incubated with a secondary antibody (1:10,000; Jackson, USA), and the secondary antibody was detected by using Tanon imaging software [4].

Statistical analysis

Data are presented as the means ± SEs. Statistical differences among groups were analyzed by one-way analysis of variance (ANOVA) with a Bonferroni post hoc test to determine group differences in all numerical data. All statistical analyses were performed with SPSS software version 19.0. P < 0.05 was considered statistically significant.

Results

Bilobalide attenuates skeletal muscle damage caused by I/R injury

Muscular tissue injury was evaluated by the H&E staining. Uninjured fibers were characterized as having well-defined borders and morphologic uniformity without holes or breaks, while injured fibers exhibited broken, fragmented fiber morphologies. Histological damage scores were assigned based on muscle fiber disorganization and degeneration and on inflammatory cell infiltration. Muscle fiber injury, neutrophil infiltration, sarcoplasm dissolution and erythrocyte diapedesis were observed in the I/R group animals but not in those of the sham group animals (Fig. 1a). Bilobalide treatment alleviated the degree of muscle injury (Fig. 1a). Consequently, the histological damage scores of the I/R group rats were higher than those of the sham group rats (Fig. 1b, p < 0.05). Bilobalide decreased histological damage scores in muscle tissue following I/R injury (Fig. 1b, p < 0.05). However, the histological damage scores were higher in the I/R + bilobalide-low group and the I/R + bilobalide-high group than in the sham group (Fig. 1b, p < 0.05). Moreover, the histological damage scores tended to be lower in the I/R + bilobalide-high group than in the I/R + bilobalide-low group, but the difference between groups was not statistically significant (Fig. 1b, p > 0.05).
In addition, skeletal muscle wet/dry ratios were determined to detect changes in tissue edema. The skeletal muscle wet/dry ratio in the I/R injury group was higher than that in the sham group (Fig. 1c, p < 0.05). The wet/dry ratios of the animals in the I/R injury groups treated with bilobalide were lower than those of the animals in the untreated I/R injury group (Fig. 1c, p < 0.05). However, the wet/dry ratios were higher in the I/R + bilobalide-low group and the I/R + bilobalide-high group than in the sham group (Fig. 1c, p < 0.05). Moreover, the wet/dry ratios tended to be lower in the I/R + bilobalide-high group than in the I/R + bilobalide-low group, but the difference between the groups was not statistically significant (Fig. 1c, p > 0.05).

Bilobalide alleviates local oxidative stress in the skeletal muscles of rats with I/R injury

NADPH oxidase activity (Fig. 2a, p < 0.05), F2-isoprostane levels (Fig. 2b, p < 0.05) and MDA levels (Fig. 2c, p < 0.05) were higher in the I/R group than in the sham group. Additionally, the tissue NADPH oxidase activity and F2-isoprostane and MDA levels were lower in the bilobalide-treated I/R groups than in the I/R group (Fig. 2a-c, p < 0.05). However, the NADPH oxidase activity and F2-isoprostane and MDA levels in the I/R + bilobalide-low group and the I/R + bilobalide-high group were higher than those in the sham group (Fig. 2a-c, p < 0.05). Moreover, the values of these parameters tended to be lower in the I/R + bilobalide-high group than in the I/R + bilobalide-low group, but the differences between the groups were not statistically significant (Fig. 2a-c, p > 0.05).
SOD (Fig. 2d, p < 0.05), CAT (Fig. 2e, p < 0.05) and GSH-Px (Fig. 2f, p < 0.05) activity levels were significantly lower in the I/R group than in the sham group. Additionally, the tissue SOD, CAT and GSH-Px activity levels were higher in the bilobalide-treated I/R groups than in the I/R group (Fig. 2d-f, p < 0.05). However, the activity of these enzymes was lower in the I/R + bilobalide-low group and the I/R + bilobalide-high group than in the sham group (Fig. 2d-f, p < 0.05). Moreover, the tissue SOD, CAT and GSH-Px activity levels tended to be higher in the I/R + bilobalide-high group than in the I/R + bilobalide-low group, but the differences between the groups were not statistically significant (Fig. 2d-f, p < 0.05).

Bilobalide ameliorates the skeletal muscle inflammatory response in rats with I/R injury

The activity of MPO in the I/R group was higher than that in the sham group (Fig. 3a, p < 0.05), which indicated the occurrence of neutrophil infiltration and inflammatory cytokine activation after I/R. Treatment with bilobalide markedly attenuated the I/R-induced increase in MPO activity (Fig. 3a, p < 0.05). However, MPO activity was higher in the I/R + bilobalide-low group and the I/R + bilobalide-high group than in the sham group (Fig. 3a, p < 0.05). Moreover, MPO activity tended to be lower in the I/R + bilobalide-high group than in the I/R + bilobalide-low group, but the difference between the groups was not statistically significant (Fig. 3a, p > 0.05).
Additionally, the levels of IL-1β (Fig. 3b, p < 0.05), TNF-α (Fig. 3c, p < 0.05) and IL-6 (Fig. 3d, p < 0.05) were significantly higher in the I/R group than in the sham group. Similar to the effects on MPO activity, bilobalide treatment attenuated the I/R-induced increases in inflammatory cytokines levels; the levels of IL-1β (Fig. 3b, p < 0.05), TNF-α (Fig. 3c, p < 0.05) and IL-6 (Fig. 3d, p < 0.05) in the bilobalide-treated I/R groups were significantly lower than the levels in the I/R group. However, the levels of IL-1β (Fig. 3b, p < 0.05), TNF-α (Fig. 3c, p < 0.05) and IL-6 (Fig. 3d, p < 0.05) were higher in the I/R + bilobalide-low group and the I/R + bilobalide-high group than in the sham group (Fig. 3a, p < 0.05). Moreover, the levels of IL-1β (Fig. 3b, p < 0.05), TNF-α (Fig. 3c, p < 0.05) and IL-6 (Fig. 3d, p < 0.05) were lower in the I/R + bilobalide-high group than in the I/R + bilobalide-low group, but the differences between the groups were not statistically significant (Fig. 3a, p > 0.05).

Bilobalide suppresses activation of the p38, ERK1/2, JNK, and NF-κB p65 pathways

As shown in Fig. 4, I/R injury alone increased the expression of phosphorylated p38 (Fig. 4b, p < 0.05), phosphorylated ERK1/2 (Fig. 4c, p < 0.05), phosphorylated JNK (Fig. 4d, p < 0.05) and NF- κB p65 (Fig. 4e, p < 0.05), while bilobalide administration significantly attenuated the I/R-induced upregulation of phosphorylated p38 (Fig. 4b, p < 0.05, vs. the I/R injury group), phosphorylated ERK1/2 (Fig. 4c, p < 0.05, vs. the I/R injury group), phosphorylated JNK (Fig. 4d, p < 0.05, vs. the I/R injury group) and NF- κB p65 (Fig. 4e, p < 0.05, vs. the I/R injury group). These findings suggest that the protective effects of bilobalide in this skeletal I/R injury model might be mediated partly through inhibition of p38, ERK1/2, JNK and NF- κB p65 pathway activation. However, the expression of phosphorylated p38 (Fig. 4b), phosphorylated ERK1/2 (Fig. 4c), phosphorylated JNK (Fig. 4d), and NF- κB p65 (Fig. 4e) was higher in the I/R + bilobalide-low group and the I/R + bilobalide-high group than in the sham group (p < 0.05). There was no significant difference in the expression of phosphorylated p38 (Fig. 4b), phosphorylated ERK1/2 (Fig. 4c), phosphorylated JNK (Fig. 4d), or NF- κB p65 (Fig. 4e) between the I/R + bilobalide-high group and the I/R + bilobalide-low group (p > 0.05).

Discussion

In this study, we initially found that bilobalide partially restored the morphology of the gastrocnemius after I/R injury and reduced tissue edema in skeletal muscle. Furthermore, we demonstrated that bilobalide could relieve oxidative stress and systemic inflammatory responses caused by I/R injury. In addition, our findings suggested that bilobalide suppressed the activation of the p38, ERK1/2, JNK, and NF- κB p65 pathways in the I/R injured skeletal muscle, suggesting that the protective effects of bilobalide might be partly mediated by suppressing the activation of MAPK/NF- κB pathway.
Previous studies have indicated that skeletal muscle I/R injury is an important clinical problem that should not be ignored [13]. At present, there are different ways to treat limb I/R injury, including physical therapy and chemical therapy. It has been reported that ischemic preconditioning [9], ischemic postconditioning [21], controlled reperfusion [22], hypothermia [23], light-emitting diode therapy [24] and some other physical therapies can relieve skeletal I/R injury [25]. In addition, several agents, such as dexamethasone [10], curcumin [26], salvianolic acid [8], silibinin [27], simvastatin [28], cyclosporine A [29], hydrogen-rich saline [30] and lipoxin A4 [4], have been shown to be effective in attenuating skeletal I/R injury. In cases of traumatic injuries in which I/R is not predictable and early intervention is desired, such strategies are not as relevant. This is especially true for severe extremity injuries. Lifesaving surgical procedures are performed in these cases with the objective of stopping hemorrhage for the preservation of vital organ function; the extremities are not the primary focus. Moreover, even though the strategies and agents mentioned above have shown some benefits in the laboratory, none have been established to have any clinical benefits. Hence, there is still a need to discover novel substances with antioxidant and anti-inflammatory capacities that can be utilized for the treatment of skeletal I/R injury.
Bilobalide can be extracted from Ginkgo biloba leaves, which are widely used in traditional Chinese medicine. EGb 761, a standardized extract from Ginkgo biloba leaves, has various pharmacological functions and has been used worldwide. Bilobalide accounts for approximately 3% of EGb 761 [31]. Otani et al. reported that bilobalide can prevent cytotoxic brain edema caused by triethyltin [32]. Others have shown that bilobalide can protect against ischemia or I/R injury-induced edema formation and that it is a potential antiedema drug [33]. In the present study, we found that bilobalide attenuated I/R injury in a skeletal I/R injury model. Histological findings indicated that there were fewer histopathologic changes in bilobalide-treated animals subjected to I/R than in untreated animals subjected to I/R. Moreover, we demonstrated that bilobalide significantly reduced edema in I/R-injured skeletal muscle.
Oxidative stress is considered to play important roles in the process of limb I/R injury [8]. Our data showed that bilobalide significantly ameliorated skeletal muscle oxidative stress induced by I/R injury by decreasing NADPH oxidase activity and F2-isoprostane and MDA levels and by enhancing CAT, GSH-Px and SOD activity. Meanwhile, antioxidative effects of bilobalide have been reported in the context of neuronal degeneration in Alzheimer’s disease [34]. Parimoo et al. showed that bilobalide can be used as a promising hepatoprotectant due to its antioxidative effects [35]. Lu et al. demonstrated that bilobalide protects melanocytes from H2O2-induced oxidative damage by increasing antioxidant expression [36]. These results indicate that the antioxidative effects of bilobalide may be important in cases of I/R-injured skeletal muscle.
Inflammatory responses are generally considered to be major causes of skeletal muscle I/R injury [4]. Puntel and colleagues have illustrated that MPO activity is an indicator of neutrophil infiltration in I/R injury in skeletal muscle [37]. Infiltrating neutrophils can also release a variety of inflammatory cytokines, such as TNF-α, IL-1β and IL-6, which play roles in inflammatory reactions [38]. Several studies have demonstrated that bilobalide acts as an anti-inflammatory mediator in cerebral I/R injury and many other inflammatory response-related diseases [3941]. In this study, we found that bilobalide could relieve systemic inflammatory responses in the skeletal muscle caused by I/R injury.
Under oxidative stress or inflammatory response conditions, the MAPK and NF- κB pathways can be activated [10]. Recent studies have shown that in some I/R injury models, including the skeletal I/R injury model, the p38, ERK1/2, JNK and p65 pathways are active [4, 8]. In the present study, we found that inhibition of these four specific cellular pathways with their specific inhibitors (P38 MAPK: SB203580; ERK: ravoxertinib; JNK: SP600125; P65 NF-κB: SC75741) alleviated apoptosis and local oxidative stress and decreased inflammatory cytokine levels in IR-injured skeletal muscle (Supplementary Figure 2). Additionally, we demonstrated that the protein levels of phosphorylated p38, phosphorylated ERK1/2, phosphorylated JNK, and p65 was significantly increased in skeletal muscle after I/R injury and that bilobalide partially inhibited p38, ERK1/2, JNK, and p65 activation, suggesting that activation of the corresponding signaling pathways might mediate some of the protective effects of bilobalide in this model. These observations are consistent with the findings of previous studies. Priyanka and colleagues showed that bilobalide abates inflammation induced by hypoxia in adipocytes via reducing activation of the NF- κB and JNK signaling pathways [40]. Zhou and colleagues showed that bilobalide inhibits the secretion of inflammatory factors in BV2 microglia in response to oxygen/glucose deprivation and reoxygenation by controlling the activation of TLR/MyD88/NF- κB pathways [41]. In other studies, however, bilobalide has failed to inhibit increases in p-ERK1/2 expression. For example, Jiang et al. proved that bilobalide could play an important role in neuroprotection against cerebral I/R injury through a mechanism related to downregulation of JNK and p38 activation but not ERK1/2 activation [42]. Previous studies have also revealed that bilobalide cannot regulate the expression of p-ERK1/2 in SH-SY5Y cells [43]. These variations in results may be associated with the different species and sources of cells or the different animal and disease models used.
There were some limitations to our study. In this study, we treated the rats with bilobalide after 3 h of ischemia and then reperfused them for 24 h. However, in some clinical cases (for example, during reattachment of a limb or flap), there is not enough time for bilobalide treatment between ischemic injury and reperfusion. We did not test whether administering bilobalide treatment after I/R injury had the same protective effects as administering it between ischemia and reperfusion. In addition, we observed involvement of the p38, ERK1/2, JNK and p65 pathways in the protective effects of bilobalide on skeletal muscle. However, the specific effects of these pathways in limb I/R injury remain to be investigated.

Conclusions

In summary, our study reveals that bilobalide alleviates skeletal muscle damage caused by I/R injury. Moreover, bilobalide protects against I/R injury-induced oxidative stress and inflammation via the MAPK/NF- κB pathways. Bilobalide may be a promising drug for I/R-injured muscle tissue.

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s12891-020-03479-9.

Acknowledgments

Zhongyang Sun especially wishes to thank his wife Xiaotong Pei, who has given him significant spiritual support over the past decade.
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. We confirm that our study have been submitted to and approved by the Experimental Animal Ethics Committee and Biomedical Ethics Committee of Anhui Medical University.
All the authors of the manuscript have approved the publication of it. And we all confirm that the work described has not been published before and it is not under consideration for publication elsewhere.

Competing interests

The authors declare that they have no competing interests.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Anhänge
Literatur
1.
Zurück zum Zitat Zhou T, Prather E, Garrison D, Zuo L. Interplay between ROS and antioxidants during ischemia-reperfusion injuries in cardiac and skeletal muscle. Int J Mol Sci. 2018;19:417.PubMedCentralCrossRef Zhou T, Prather E, Garrison D, Zuo L. Interplay between ROS and antioxidants during ischemia-reperfusion injuries in cardiac and skeletal muscle. Int J Mol Sci. 2018;19:417.PubMedCentralCrossRef
2.
Zurück zum Zitat Kobayashi J, Murata I. Nitrite as a pharmacological intervention for the successful treatment of crush syndrome. Physiol Rep. 2018;6:e13633.PubMedCentralCrossRef Kobayashi J, Murata I. Nitrite as a pharmacological intervention for the successful treatment of crush syndrome. Physiol Rep. 2018;6:e13633.PubMedCentralCrossRef
3.
Zurück zum Zitat Cheng Y, Si D, Fan C, Cai L, Gao C, Jiang P, et al. SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury. Apoptosis. 2016;21:905–16.PubMedCrossRef Cheng Y, Si D, Fan C, Cai L, Gao C, Jiang P, et al. SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury. Apoptosis. 2016;21:905–16.PubMedCrossRef
4.
Zurück zum Zitat Zong H, Li X, Lin H, Hou C, Ma F. Lipoxin A4 pretreatment mitigates skeletal muscle ischemia-reperfusion injury in rats. Am J Transl Res. 2017;9:1139–50.PubMedPubMedCentral Zong H, Li X, Lin H, Hou C, Ma F. Lipoxin A4 pretreatment mitigates skeletal muscle ischemia-reperfusion injury in rats. Am J Transl Res. 2017;9:1139–50.PubMedPubMedCentral
5.
Zurück zum Zitat Lustgarten MS, Jang YC, Liu YH, Qi WB, Qin YJ, Dahia PL, et al. MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging. Aging Cell. 2011;3:493–505.CrossRef Lustgarten MS, Jang YC, Liu YH, Qi WB, Qin YJ, Dahia PL, et al. MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging. Aging Cell. 2011;3:493–505.CrossRef
6.
Zurück zum Zitat Bhattacharya A, Hamilton R, Jernigan A, Zhang Y, Sabia M, Rahman MM, et al. Genetic ablation of 12/15-lipoxygenase but not 5-lipoxygenase protects against denervation-induced muscle atrophy. Free Radical Bio Med. 2014;67:30–40.CrossRef Bhattacharya A, Hamilton R, Jernigan A, Zhang Y, Sabia M, Rahman MM, et al. Genetic ablation of 12/15-lipoxygenase but not 5-lipoxygenase protects against denervation-induced muscle atrophy. Free Radical Bio Med. 2014;67:30–40.CrossRef
7.
Zurück zum Zitat Rahman M, Halade GV, Bhattacharya A, Fernandes G. The fat-1 transgene in mice increases antioxidant potential, reduces pro-inflammatory cytokine levels, and enhances PPAR-gamma and SIRT-1 expression on a calorie restricted diet. Oxidative Med Cell Longev. 2009;2:307–16.CrossRef Rahman M, Halade GV, Bhattacharya A, Fernandes G. The fat-1 transgene in mice increases antioxidant potential, reduces pro-inflammatory cytokine levels, and enhances PPAR-gamma and SIRT-1 expression on a calorie restricted diet. Oxidative Med Cell Longev. 2009;2:307–16.CrossRef
8.
Zurück zum Zitat Xiang Y, Ye S, Cai C, Chen J, Zhao X, Zhu N, et al. Salvianolic acid a attenuates limb ischemia/reperfusion injury in skeletal muscle of rats. Biomed Pharmacother. 2018;97:551–6.PubMedCrossRef Xiang Y, Ye S, Cai C, Chen J, Zhao X, Zhu N, et al. Salvianolic acid a attenuates limb ischemia/reperfusion injury in skeletal muscle of rats. Biomed Pharmacother. 2018;97:551–6.PubMedCrossRef
9.
Zurück zum Zitat Kocman EA, Ozatik O, Sahin A, Guney T, Kose AA, Dag I, et al. Effects of ischemic preconditioning protocols on skeletal muscle ischemia-reperfusion injury. J Surg Res. 2015;193:942–52.PubMedCrossRef Kocman EA, Ozatik O, Sahin A, Guney T, Kose AA, Dag I, et al. Effects of ischemic preconditioning protocols on skeletal muscle ischemia-reperfusion injury. J Surg Res. 2015;193:942–52.PubMedCrossRef
10.
Zurück zum Zitat Corrick RM, Tu H, Zhang D, Barksdale AN, Muelleman RL, Wadman MC, et al. Dexamethasone protects against tourniquet-induced acute ischemia-reperfusion injury in mouse hindlimb. Front Physiol. 2018;20:244.CrossRef Corrick RM, Tu H, Zhang D, Barksdale AN, Muelleman RL, Wadman MC, et al. Dexamethasone protects against tourniquet-induced acute ischemia-reperfusion injury in mouse hindlimb. Front Physiol. 2018;20:244.CrossRef
11.
Zurück zum Zitat Zhang J, Xia J, Zhang Y, Xiao F, Wang J, Gao H, et al. HMGB1-TLR4 signaling participates in renal ischemia reperfusion injury and could be attenuated by dexamethasone-mediated inhibition of the ERK/NF-κB pathway. Am J Transl Res. 2016;10:4054–67. Zhang J, Xia J, Zhang Y, Xiao F, Wang J, Gao H, et al. HMGB1-TLR4 signaling participates in renal ischemia reperfusion injury and could be attenuated by dexamethasone-mediated inhibition of the ERK/NF-κB pathway. Am J Transl Res. 2016;10:4054–67.
12.
Zurück zum Zitat Zheng DY, Zhou M, Jin J, He M, Wang Y, Du J, et al. Inhibition of P38 MAPK downregulates the expression of IL-1β to protect lung from acute injury in intestinal ischemia reperfusion rats. Mediat Inflam. 2016;2016:9348037. Zheng DY, Zhou M, Jin J, He M, Wang Y, Du J, et al. Inhibition of P38 MAPK downregulates the expression of IL-1β to protect lung from acute injury in intestinal ischemia reperfusion rats. Mediat Inflam. 2016;2016:9348037.
13.
Zurück zum Zitat Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, et al. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signaling. Pharmacol Res. 2017;119:137–48.PubMedCrossRef Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, et al. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signaling. Pharmacol Res. 2017;119:137–48.PubMedCrossRef
14.
Zurück zum Zitat Yu H, Shi L, Qi G, Zhao S, Gao Y, Li Y. Gypenoside protects cardiomyocytes against ischemia-reperfusion injury via the inhibition of mitogen-activated protein kinase mediated nuclear factor kappa B pathway in vitro and in vivo. Front Pharmacol. 2016;7:148.PubMedPubMedCentralCrossRef Yu H, Shi L, Qi G, Zhao S, Gao Y, Li Y. Gypenoside protects cardiomyocytes against ischemia-reperfusion injury via the inhibition of mitogen-activated protein kinase mediated nuclear factor kappa B pathway in vitro and in vivo. Front Pharmacol. 2016;7:148.PubMedPubMedCentralCrossRef
15.
Zurück zum Zitat Sui RX, Miao Q, Wang J, Wang Q, Song LJ, Yu JW, et al. Protective and therapeutic role of bilobalide in cuprizone-induced demyelination. Int Immunopharmacol. 2019;66:69–81.PubMedCrossRef Sui RX, Miao Q, Wang J, Wang Q, Song LJ, Yu JW, et al. Protective and therapeutic role of bilobalide in cuprizone-induced demyelination. Int Immunopharmacol. 2019;66:69–81.PubMedCrossRef
16.
Zurück zum Zitat Xiang J, Zhang J, Cai X, Yang F, Zhu W, Zhang W, et al. Bilobalide protects astrocytes from oxygen and glucose deprivation-induced oxidative injury by upregulating manganese superoxide dismutase. Phytother Res. 2019;33:2329–36.PubMedCrossRef Xiang J, Zhang J, Cai X, Yang F, Zhu W, Zhang W, et al. Bilobalide protects astrocytes from oxygen and glucose deprivation-induced oxidative injury by upregulating manganese superoxide dismutase. Phytother Res. 2019;33:2329–36.PubMedCrossRef
17.
Zurück zum Zitat Wu R, Shui L, Wang S, Song Z, Tai F. Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice. Behav Pharmacol. 2016;27:596–605.PubMedCrossRef Wu R, Shui L, Wang S, Song Z, Tai F. Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice. Behav Pharmacol. 2016;27:596–605.PubMedCrossRef
18.
Zurück zum Zitat Goldie M, Dolan S. Bilobalide, a unique constituent of Ginkgo biloba, inhibits inflammatory pain in rats. Behav Pharmacol. 2013;24:298–306.PubMedCrossRef Goldie M, Dolan S. Bilobalide, a unique constituent of Ginkgo biloba, inhibits inflammatory pain in rats. Behav Pharmacol. 2013;24:298–306.PubMedCrossRef
19.
Zurück zum Zitat Schwarzkopf TM, Koch KA, Klein J. Neurodegeneration after transient brain ischemia in aged mice: beneficial effects of bilobalide. Brain Res. 2013;1529:178–87.PubMedCrossRef Schwarzkopf TM, Koch KA, Klein J. Neurodegeneration after transient brain ischemia in aged mice: beneficial effects of bilobalide. Brain Res. 2013;1529:178–87.PubMedCrossRef
20.
Zurück zum Zitat Erkanli K, Kayalar N, Erkanli G, Ercan F, Sener G, Kirali K. Melatonin protects against ischemia/reperfusion injury in skeletal muscle. J Pineal Res. 2005;3:238–42.CrossRef Erkanli K, Kayalar N, Erkanli G, Ercan F, Sener G, Kirali K. Melatonin protects against ischemia/reperfusion injury in skeletal muscle. J Pineal Res. 2005;3:238–42.CrossRef
21.
Zurück zum Zitat McAllister SE, Ashrafpour H, Cahoon N, Huang N, Moses MA, Neligan PC, et al. Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism. Am J Physiol-Reg I. 2008;95:R681–9. McAllister SE, Ashrafpour H, Cahoon N, Huang N, Moses MA, Neligan PC, et al. Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism. Am J Physiol-Reg I. 2008;95:R681–9.
22.
Zurück zum Zitat Hamrin K, Rosdahl H, Ungerstedt U, Henriksson J. Microdialysis in human skeletal muscle: effects of adding a colloid to the perfusate. J Appl Physiol. 2002;92:385–93.PubMedCrossRef Hamrin K, Rosdahl H, Ungerstedt U, Henriksson J. Microdialysis in human skeletal muscle: effects of adding a colloid to the perfusate. J Appl Physiol. 2002;92:385–93.PubMedCrossRef
23.
Zurück zum Zitat Simon MA, Tibbits EM, Hoareau GL, Davidson AJ, DeSoucy ES, Faulconer ER, et al. Lower extremity cooling reduces ischemia-reperfusion injury following zone 3 reboa in a porcine hemorrhage model. J Trauma Acute Care. 2018;85:512–8.CrossRef Simon MA, Tibbits EM, Hoareau GL, Davidson AJ, DeSoucy ES, Faulconer ER, et al. Lower extremity cooling reduces ischemia-reperfusion injury following zone 3 reboa in a porcine hemorrhage model. J Trauma Acute Care. 2018;85:512–8.CrossRef
24.
Zurück zum Zitat Takhtfooladi MA, Shahzamani M, Takhtfooladi HA, Moayer F, Allahverdi A. Effects of light-emitting diode (LED) therapy on skeletal muscle ischemia reperfusion in rats. Laser Med Sci. 2015;30:311–6.CrossRef Takhtfooladi MA, Shahzamani M, Takhtfooladi HA, Moayer F, Allahverdi A. Effects of light-emitting diode (LED) therapy on skeletal muscle ischemia reperfusion in rats. Laser Med Sci. 2015;30:311–6.CrossRef
25.
Zurück zum Zitat Zeng Q, Fu Q, Wang X, Zhao Y, Liu H, Li Z, et al. Protective effects of sonic hedgehog against ischemia/reperfusion injury in mouse skeletal muscle via AKT/mTOR/p70S6K signaling. Cell Physiol Biochem. 2018;43:1813–28.CrossRef Zeng Q, Fu Q, Wang X, Zhao Y, Liu H, Li Z, et al. Protective effects of sonic hedgehog against ischemia/reperfusion injury in mouse skeletal muscle via AKT/mTOR/p70S6K signaling. Cell Physiol Biochem. 2018;43:1813–28.CrossRef
26.
Zurück zum Zitat Avci G, Kadioglu H, Sehirli AO, Bozkurt S, Guclu O, Arslan E, et al. Curcumin protects against ischemia/reperfusion injury in rat skeletal muscle. J Surg Res. 2012;172:e39–46.PubMedCrossRef Avci G, Kadioglu H, Sehirli AO, Bozkurt S, Guclu O, Arslan E, et al. Curcumin protects against ischemia/reperfusion injury in rat skeletal muscle. J Surg Res. 2012;172:e39–46.PubMedCrossRef
27.
Zurück zum Zitat Ergun Y, Kurutas EB, Atalay F, Alici T. Effects of silibinin and ethanol on skeletal muscle ischemia-reperfusion injury. Acta Cir Bras. 2013;28:179–84.PubMedCrossRef Ergun Y, Kurutas EB, Atalay F, Alici T. Effects of silibinin and ethanol on skeletal muscle ischemia-reperfusion injury. Acta Cir Bras. 2013;28:179–84.PubMedCrossRef
28.
Zurück zum Zitat Zhao Y, Feng Q, Huang Z, Li W, Chen B, Jiang L, et al. Simvastatin inhibits inflammation in ischemia-reperfusion injury. Inflammation. 2014;37:1865–75.PubMedCrossRef Zhao Y, Feng Q, Huang Z, Li W, Chen B, Jiang L, et al. Simvastatin inhibits inflammation in ischemia-reperfusion injury. Inflammation. 2014;37:1865–75.PubMedCrossRef
29.
Zurück zum Zitat Pottecher J, Kindo M, Chamaraux-Tran T, Charles A, Lejay A, Kemmel V, et al. Skeletal muscle ischemia-reperfusion injury and cyclosporine a in the aging rat. Fund Clin Pharmacol. 2016;30:216–25.CrossRef Pottecher J, Kindo M, Chamaraux-Tran T, Charles A, Lejay A, Kemmel V, et al. Skeletal muscle ischemia-reperfusion injury and cyclosporine a in the aging rat. Fund Clin Pharmacol. 2016;30:216–25.CrossRef
30.
Zurück zum Zitat Huang T, Wang W, Tu C, Yang Z, Bramwell D, Sun X. Hydrogen-rich saline attenuates ischemia-reperfusion injury in skeletal muscle. J Surg Res. 2015;194:471–80.PubMedCrossRef Huang T, Wang W, Tu C, Yang Z, Bramwell D, Sun X. Hydrogen-rich saline attenuates ischemia-reperfusion injury in skeletal muscle. J Surg Res. 2015;194:471–80.PubMedCrossRef
31.
Zurück zum Zitat Hua J, Yin N, Yang B, Zhang J, Ding J, Fan Y, et al. Ginkgolide B and bilobalide ameliorate neural cell apoptosis in α-synuclein aggregates. Biomed Pharmacother. 2017;96:792–7.PubMedCrossRef Hua J, Yin N, Yang B, Zhang J, Ding J, Fan Y, et al. Ginkgolide B and bilobalide ameliorate neural cell apoptosis in α-synuclein aggregates. Biomed Pharmacother. 2017;96:792–7.PubMedCrossRef
32.
Zurück zum Zitat Otani M, Chatterjee SS, Gabard B, Kreutzberg GW. Effect of an extract of Ginkgo biloba on triethyltin-induced cerebral edema. Acta Neuropathol. 1986;69:54–65.PubMedCrossRef Otani M, Chatterjee SS, Gabard B, Kreutzberg GW. Effect of an extract of Ginkgo biloba on triethyltin-induced cerebral edema. Acta Neuropathol. 1986;69:54–65.PubMedCrossRef
33.
Zurück zum Zitat Mdzinarishvili A, Kiewert C, Kumar V, Hillert M, Klein J. Bilobalide prevents ischemia-induced edema formation in vitro and in vivo. Neuroscience. 2007;144:217–22.PubMedCrossRef Mdzinarishvili A, Kiewert C, Kumar V, Hillert M, Klein J. Bilobalide prevents ischemia-induced edema formation in vitro and in vivo. Neuroscience. 2007;144:217–22.PubMedCrossRef
34.
Zurück zum Zitat Blecharz-Klin K, Piechal A, Joniec I, Pyrzanowska J, Widy-Tyszkiewicz E. Pharmacological and biochemical effects of Ginkgo biloba extract on learning, memory consolidation and motor activity in old rats. Acta Neurobiol Exp. 2009;69:217–31. Blecharz-Klin K, Piechal A, Joniec I, Pyrzanowska J, Widy-Tyszkiewicz E. Pharmacological and biochemical effects of Ginkgo biloba extract on learning, memory consolidation and motor activity in old rats. Acta Neurobiol Exp. 2009;69:217–31.
35.
Zurück zum Zitat Parimoo HA, Sharma R, Patil RD, Sharma OP, Kumar P, Kumar N. Hepatoprotective effect of Ginkgo biloba leaf extract on lantadenes-induced hepatotoxicity in Guinea pigs. Toxicon. 2014;81:1–12.PubMedCrossRef Parimoo HA, Sharma R, Patil RD, Sharma OP, Kumar P, Kumar N. Hepatoprotective effect of Ginkgo biloba leaf extract on lantadenes-induced hepatotoxicity in Guinea pigs. Toxicon. 2014;81:1–12.PubMedCrossRef
36.
Zurück zum Zitat Lu L, Wang S, Fu L, Liu D, Zhu Y, Xu A. Bilobalide protection of normal human melanocytes from hydrogen peroxide-induced oxidative damage via promotion of antioxidase expression and inhibition of endoplasmic reticulum stress. Clin Exp Dermatol. 2016;41:64–73.PubMedCrossRef Lu L, Wang S, Fu L, Liu D, Zhu Y, Xu A. Bilobalide protection of normal human melanocytes from hydrogen peroxide-induced oxidative damage via promotion of antioxidase expression and inhibition of endoplasmic reticulum stress. Clin Exp Dermatol. 2016;41:64–73.PubMedCrossRef
37.
Zurück zum Zitat Puntel GO, Carvalho NR, Amaral GP, Lobato LD, Silveira SO, Daubermann MF, et al. Therapeutic cold: an effective kind to modulate the oxidative damage resulting of a skeletal muscle contusion. Free Radic Res. 2011;45:125–38.PubMedCrossRef Puntel GO, Carvalho NR, Amaral GP, Lobato LD, Silveira SO, Daubermann MF, et al. Therapeutic cold: an effective kind to modulate the oxidative damage resulting of a skeletal muscle contusion. Free Radic Res. 2011;45:125–38.PubMedCrossRef
38.
Zurück zum Zitat Bonaventura A, Montecucco F, Dallegri F. Cellular recruitment in myocardial ischaemia/reperfusion injury. Eur J Clin Investig. 2016;46:590–601.CrossRef Bonaventura A, Montecucco F, Dallegri F. Cellular recruitment in myocardial ischaemia/reperfusion injury. Eur J Clin Investig. 2016;46:590–601.CrossRef
39.
Zurück zum Zitat Priyanka A, Nisha VM, Anusree SS, Raghu KG. Bilobalide attenuates hypoxia induced oxidative stress, inflammation, and mitochondrial dysfunctions in 3T3-L1 adipocytes via its antioxidant potential. Free Radic Res. 2014;48:1206–17.PubMedCrossRef Priyanka A, Nisha VM, Anusree SS, Raghu KG. Bilobalide attenuates hypoxia induced oxidative stress, inflammation, and mitochondrial dysfunctions in 3T3-L1 adipocytes via its antioxidant potential. Free Radic Res. 2014;48:1206–17.PubMedCrossRef
40.
Zurück zum Zitat Priyanka A, Sindhu G, Shyni GL, Preetha Rani MR, Nisha VM, Raghu KG. Bilobalide abates inflammation, insulin resistance and secretion of angiogenic factors induced by hypoxia in 3T3-L1 adipocytes by controlling NF-κB and JNK activation. Int Immunopharmacol. 2017;42:209–17.PubMedCrossRef Priyanka A, Sindhu G, Shyni GL, Preetha Rani MR, Nisha VM, Raghu KG. Bilobalide abates inflammation, insulin resistance and secretion of angiogenic factors induced by hypoxia in 3T3-L1 adipocytes by controlling NF-κB and JNK activation. Int Immunopharmacol. 2017;42:209–17.PubMedCrossRef
41.
Zurück zum Zitat Zhou JM, Gu SS, Mei WH, Zhou J, Wang ZZ, Xiao W. Ginkgolides and bilobalide protect BV2 microglia cells against OGD/reoxygenation injury by inhibiting TLR2/4 signaling pathways. Cell Stress Chaperones. 2016;21:1037–53.PubMedPubMedCentralCrossRef Zhou JM, Gu SS, Mei WH, Zhou J, Wang ZZ, Xiao W. Ginkgolides and bilobalide protect BV2 microglia cells against OGD/reoxygenation injury by inhibiting TLR2/4 signaling pathways. Cell Stress Chaperones. 2016;21:1037–53.PubMedPubMedCentralCrossRef
42.
Zurück zum Zitat Jiang M, Li J, Peng Q, Liu Y, Liu W, Luo C, et al. Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. J Neuroinflammation. 2014;11:167.PubMedPubMedCentralCrossRef Jiang M, Li J, Peng Q, Liu Y, Liu W, Luo C, et al. Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. J Neuroinflammation. 2014;11:167.PubMedPubMedCentralCrossRef
43.
Zurück zum Zitat Shi C, Wu F, Yew DT, Xu J, Zhu Y. Bilobalide prevents apoptosis through activation of the PI3K/Akt pathway in SH-SY5Y cells. Apoptosis. 2010;15:715–27.PubMedCrossRef Shi C, Wu F, Yew DT, Xu J, Zhu Y. Bilobalide prevents apoptosis through activation of the PI3K/Akt pathway in SH-SY5Y cells. Apoptosis. 2010;15:715–27.PubMedCrossRef
Metadaten
Titel
Bilobalide protects against ischemia/reperfusion-induced oxidative stress and inflammatory responses via the MAPK/NF-κB pathways in rats
verfasst von
Ying Li
Jiliang Jiang
Liangcheng Tong
Tingting Gao
Lei Bai
Qing Xue
Jianxin Xing
Qin Wang
Haoran Lyu
Min Cai
Zhongyang Sun
Publikationsdatum
01.12.2020
Verlag
BioMed Central
Erschienen in
BMC Musculoskeletal Disorders / Ausgabe 1/2020
Elektronische ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-020-03479-9

Weitere Artikel der Ausgabe 1/2020

BMC Musculoskeletal Disorders 1/2020 Zur Ausgabe

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen. 
» Jetzt entdecken

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Arthroskopie kann Knieprothese nicht hinauszögern

25.04.2024 Gonarthrose Nachrichten

Ein arthroskopischer Eingriff bei Kniearthrose macht im Hinblick darauf, ob und wann ein Gelenkersatz fällig wird, offenbar keinen Unterschied.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Ärztliche Empathie hilft gegen Rückenschmerzen

23.04.2024 Leitsymptom Rückenschmerzen Nachrichten

Personen mit chronischen Rückenschmerzen, die von einfühlsamen Ärzten und Ärztinnen betreut werden, berichten über weniger Beschwerden und eine bessere Lebensqualität.

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.