Elsevier

Phytomedicine

Volume 16, Issue 10, October 2009, Pages 976-981
Phytomedicine

Short Communication
The protective efficacy of magnolol in hind limb ischemia-reperfusion injury

https://doi.org/10.1016/j.phymed.2009.03.001Get rights and content

Abstract

We investigated the protective effects of magnolol, an active antioxidant and free radical scavenger extracted from Magnolia officinalis, in a hind limb ischemic-reperfusion animal model. Adult male Spraque-Dawley rats were subjected to hind limb ischemic insult for 2 hours and were intravenously treated with magnolol at 0.01 mg/kg (n=8), 0.3 mg/kg (n=8) mg/kg or 1 mg/kg (n=8) mg/kg, or vehicle (n=8). At 24 h post-insult, the levels of nitrite/nitrate (NOX), malondialdehyde (MDA) and myeloperoxidase (MPO), as well as the degree of muscle damage, were assessed. Relative to controls, animals treated with magnolol (0.3 and 1 mg/kg) had attenuated muscular inflammation, edema and damage. Magnolol (0.3–1 mg/kg) also effectively reduced postischemic rises in the MDA, NOx and MPO levels (p<0.05, respectively). Magnolol administrated at 0.01 mg/kg, however, failed to protect against the ischemic-perfusion limb injury. In addition, magnolol (0.01–1 mg/kg) did not affect local muscular blood reperfusion or other physiological parameters, including hematocrit, glucose, arterial blood gases and mean arterial blood pressure. Thus, intravenous administration with magnolol at 0.3–1 mg/kg protects against ischemic limb damage in rats. This cytoprotection may be attributed to its antioxidant, anti-nitrosative and anti-inflammatory actions.

Introduction

Ischemia-reperfusion injury (IRI) occurs in a variety of clinical conditions such as coronary arterial disease, thrombolytic therapy, balloon angioplasty, cardiopulmonary bypass, occlusive arterial disease (aortic and peripheral arterial cross-clamping), stroke, tourniquet application, myocutaneous tissue transfer, and replantation of amputated parts. Following ischemia, reperfusion of blood flow to the damaged tissues further accelerates initial tissue injury (Ambrosio and Tritto, 1999). The oxygen- and nitrogen-derived free radical (OFR and NFR)-induced cell injury plays a pivotal role in the pathogenesis of such injury. During reperfusion, superoxide (O2), hydrogen peroxide (H2O2) and hydroxyl radical (OH) are excessively produced and damage normal cell functions by destroying their antioxidant systems (Cuzzocrea et al., 2001, Cuzzocrea et al., 2004). Similarly, reperfusion damage of ischemic skeletal muscle cells also include formation of NFR as the antioxidant reserve is deceased and oxidative/nitrosative production is increased following limb ischemic-reperfusion (Cuzzocrea et al., 2004). Hence, exogenous administration of pharmacological reagents itself or those promote natural antioxidant systems has been regarded as a useful strategy to prevent IRI. A variety of antioxidants such as superoxide dismutase (SOD), catalase (CAT), dimethyl sulfoxide (DMSO), dimethylthiourea (DMTU), mannitol, vitamin A, C and E, allopurinol, desferrioxamine, and glutathione (GSH) have been proven to attenuate IRI in different organs.

Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, is reported to have a variety of pharmacological activities, including antioxidant, anti-inflammatory and anti-tumor effects (Shen et al., 1998; Chen et al., 2001, Chen et al., 2003; Wang et al., 2002; Lee et al., 2005). Magnolol has emerged as a useful antioxidant, and its potential protective effect against IRI has been investigated in a variety of the IRI models, including the heart, intestine, liver and brain (Chiu et al., 1999; Lee et al., 2000, Lee et al., 2001; Loong et al., 2001; Chang et al., 2003). Accordingly, we proposed that magnolol could protect against ischemic hind limb damage. In the present study, we investigated whether pretreatment with magnolol could attenuate tourniquet-induced skeletal muscle ischemia reperfusion injury in a rat model. Additionally, we evaluated the possible contributory role of antioxidant, anti-nitrosative and anti-inflammatory effects of magnolol in this model.

Section snippets

Plant material and magnolol preparation

Magnolol (Nacalai Tesque, Kyoto, Japan) was dissolved in polyethylene glycol (PEG 400; Sigma Chemical Co., St Louis, MO). Fresh drug solutions were prepared daily. The controls received the vehicle only.

Experimental animals

Male Sprague-Dawley rats, weighing 240–300 g, were supplied from the Charles River Technology, Taiwan. Rats were allowed free access to food and water before and after surgery. The experimental protocol was approved by the committee of Animal Research of China Medical University.

Hind limb ischemia-reperfusion injury model

Rats were

Effects of magnolol on local blood flow and core temperature

Before introducing limb ischemia, the affected limb had normal local blood flow. Local blood flow was, however, decreased to a level of 25.0–31.2% of baseline after the initiation of ischemia, but returned to 91.3–95.3% of baseline values after the onset of reperfusion. Compared with controls, magnolol-treated animals did not have significant changes in post-insult core temperatures, and magnolol did not significantly affect the LCBF as assessed before and within 24 h after treatment (Fig. 1; p

Discussion

Our results demonstrated that magnolol, given intravenously at 0.3–1.0 mg/kg, but not 0.01 mg/kg, protected against ischemia-reperfusion limb injury by decreasing oxidative and nitrosative stress, as determined by MDA and NO levels, and by attenuating inflammatory reactions, as assessed by MPO activity. Consequently, magnolol-treated animals had decreased tissue damage and neutrophil and macrophage infiltrations in the ischemic limb. This cytoprotection could not be accounted for by changes in

Conclusion

In summary, we have demonstrated that magnolol protects against ischemic-reperfusion limb injury. This protection is at least in part mediated by its anti-oxidant, free radical-scavenging and anti-inflammatory action, in addition to its possible direct cytoprotective ability.

Acknowledgments

This research was supported by grants from the National Science Council of Taiwan (94-2320-B-039-027 & 95-2320-B-039-015) and China Medical University (CMU94-148 & CMU95-105), Taichung, Taiwan.

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