Cardioprotective Effects of Alpha-Lipoic Acid on Myocardial Reperfusion Injury: Suppression of Reactive Oxygen Species Generation and Activation of Mitogen-Activated Protein Kinase

Abstract

Background and ObjectivesReactive oxygen species (ROS) and mitogen-activated protein (MAP) kinase play an important role in the development of myocardial reperfusion injury. In this study, we examined whether treatment with alpha-lipoic acid (ALA) before reperfusion could prevent myocardial reperfusion injury in vivo.Materials and MethodsSprague-Dawley rats were subjected to a 45-minute left anterior descending coronary artery ligation followed by 45- or 10-minute reperfusion. ALA was administered 10 minutes prior to reperfusion. The infarct size ratio of the infarct area to the ischemic area at risk, was measured based on 10, 25, 50, and 100 mg/kg of ALA, with propidium iodide (PI) fluorescence. Apoptosis was evaluated by TdT-mediated dUDP nick end labeling (TUNEL) staining. The generation of intracellular ROS was evaluated using the fluorogenic probe, dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Western blot analysis was performed for MAP kinase (pERK 1/2 and pJNK 1/2) activity.ResultsThe infarct size, according to ALA dose, was significantly suppressed 29.1% with ALA 25 mg/kg (p<0.0001), 41.5% with 50 mg/kg (p<0.05), and 41.4% with 100 mg/kg (p<0.05) compared to the controls (54.3%). However, the results were not significantly different with 47.2% of the ALA 10 mg/kg (p=0.192). A few apoptotic nucleoli were detected in the ALA 25 mg/kg group, but were frequently detected in the control group. The ROS generation was significantly suppressed (p<0.0001), the activity of pERK 1/2 was significantly increased (p<0.05) and the activity of pJNK 1/2 was significantly decreased (p<0.05) in the ALA 25 mg/kg group compared to the controls.ConclusionThe results of this study suggested that adequate doses of ALA before reperfusion was effective for the prevention of myocardial reperfusion injury in vivo. This cardioprotective activity of ALA might be associated with an anti-apoptotic effect of ALA via suppression of ROS generation, increase of pERK 1/2 and decrease of pJNK 1/2 activity.

α-lipoic acid protects against cerebral ischemia/reperfusion-induced injury in rats

“…In previous decades, using several different experimental models of I/R, studies have demonstrated the protective effects of LA against I/R-induced injury, including myocardial injury (7), peripheral nerve injury (8), testicular injury (9) and retinal injury (10). In addition, it has been reported that LA can activate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways to induce protection against I/R injury in other organs (11)(12)(13) to the best of our knowledge, few studies were reported to address whether LA has neuroprotective effects against cerebral I/R-induced injury and its potential mechanisms. In the present study, the neuroprotective effects of LA in rats were investigated with 90 min middle cerebral artery occlusion (MCAO)/24 h reperfusion-induced injury.…”

Lipoic Acid in the Prevention of Acute Kidney Injury

“…In addition to anti-ROS and anti-RNOS generation involving hypoxic/reoxygenation and peroxidative damage, multiple beneficial effects (e.g., anti-IRI, anti-apoptotic, anti-inflammatory and anti-enzyme effects; fig. 3) have been reported in animal models associated with LA administration [18,19,20,21,22,23,31,32]. These results indicate that LA therapy may serve as a novel treatment modality in clinical setting.…”

“…Pretreatment of rats with schisandrin B (a Chinese herb as an antioxidant) and α-LA recovered the contractile force, inhibited the leakage of lactate dehydrogenase (LDH) and increased myocardial levels of cellular non-enzymatic antioxidants, such as GSH, vitamin C (ascorbic acid) and vitamin E (α-tocopherol) [19]. Pretreatment of myocardial IRI rat model with α-LA also reduced the infarct size, and the effect may be attributed to decreased myocardial apoptosis via suppression of ROS generation and mitogen-activated protein kinase (MAPK) activity (increased activity of pERK1/2 and decreased activity of pJNK1/2) [20]. Administration of LA before reperfusion in rats has shown to protect against myocardial IRI via antioxidant, anti-apoptotic, anti-inflammatory and antioxidant enzyme effects [21].…”

“…In this context, LA has been shown to improve glucose and ascorbate handling, increase endothelial nitric oxide synthase activity, activate phase II detoxification via the transcription factor Nrf2 and lower expression of matrix metalloproteinase-9 and vascular cell adhesion molecule-1 through repression of nuclear factor-κB (NF-κB) [17]. In addition, animal studies have revealed that myocardial IRI [18,19,20,21,22,23] and renal IRI [24,25,26,27] could be protected by a naturally occurring cellular antioxidant LA, without being toxic to rats [28,29]. The mechanisms whereby LA exerts its protective effects are not entirely understood, but may be related to the phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2 pathway [23] and the PI3-kinase/Akt pathway, as ischemic preconditioning (IPC) reduces IRI of the rat liver via these pathways [30].…”

Alpha-Lipoic Acid for the Prevention of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography: The ALIVE Study - A Prospective Randomized Trial

“…tumor necrosis factor-α, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 [28]. Some experimental studies have demonstrated that ALA restores renal function, limits glomerular mesangial matrix expansion, reduces glomerulosclerosis, and prevents ischemia-reperfusion-induced renal and cardiac injury in animal models [29,30,31,32,33]. …”