Elsevier

Neuroscience

Volume 281, 5 December 2014, Pages 251-257
Neuroscience

Alpha-lipoic acid upregulates SIRT1-dependent PGC-1α expression and protects mouse brain against focal ischemia

https://doi.org/10.1016/j.neuroscience.2014.09.058Get rights and content

Highlights

  • Alpha-lipoic acid provided defense against cerebral ischemia injury in mice.

  • Alpha-lipoic acid exerted effect of anti-oxidative stress in pMCAO mice.

  • Alpha-lipoic acid upregulates SIRT1-dependent PGC-1α expression.

Abstract

Background and object

Silent mating type information regulation 2 homolog 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) which attenuates oxidative damage. Alpha-lipoic acid (ALA) has been proven to protect the rat brain against cerebral ischemia injury by reducing oxidative stress. However, the underlying mechanisms are poorly understood. In this study, we investigated the potential neuroprotection and the possible role of ALA in SIRT1 pathway.

Methods

Male CD-1 mice were randomly assigned to three groups: Sham, permanent middle cerebral artery occlusion (pMCAO) and ALA group (ALA, 50 mg/kg). ALA was administered intraperitoneally 30 min prior to ischemia in the ALA group. Neurological deficit, infarct volume, and brain edema were detected at 24 h after cerebral ischemia. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of SIRT1 and PGC-1α. Activities of superoxide dismutase (SOD) were measured by assay kits.

Results

Compared with the pMCAO group, the ALA group significantly ameliorated neurological deficit, lessened infarct volume and brain edema, increased the expression of SIRT1, PGC-1α and activities of SOD (P < 0.05).

Conclusions

ALA protected the mouse brain against ischemic damage, and this protection may be through up-regulating SIRT1-dependent PGC-1α expression.

Introduction

Ischemic stroke is a major neurological disorder and a leading cause of death and disability worldwide. Due to the lack of effective therapies, ischemic stroke is still a major medical problem urgently needed to be further studied. Accumulating evidence indicated that oxidative stress represents a key element in the occurrence and development of ischemic brain damage that results in cell damage and death (Gursoy-Ozdemir et al., 2004, Ceulemans et al., 2010). Excessive accumulation of reactive oxygen species (ROS) such as free radicals produced in cerebral ischemia could activate diverse signaling pathways and result in oxidative damage (Niizuma et al., 2009). Administering antioxidants may be one of the most promising avenues for stroke therapy (Yang et al., 2009, Chen et al., 2012a).

Silent mating-type information regulation 2 homolog 1 (SIRT1) is a crucial member of the sirtuin family of NAD+-dependent enzymes, which are related to oxidative stress response. Resveratrol as agonist of SIRT1 has already been confirmed with neuroprotection in cerebral ischemia (Raval et al., 2008, Ji et al., 2012). SIRT1 could directly affect peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) activity through phosphorylation and deacetylation (Cantó and Auwerx, 2009a). PGC-1α and other members of the PGC-1 family are potent stimulators of mitochondrial respiration and gene transcription in liver, heart, skeletal muscle and neurons (Wareski et al., 2009). Up-regulating PGC-1α could reduce neuronal death by alleviating oxidative stress (St-Pierre et al., 2006).

Alpha-lipoic acid (ALA, 1,2-dithiolane-3-pentanoic acid) is a free radical scavenger in its oxidized state, which functions as an essential co-factor in the mitochondrial dehydrogenase complexes. ALA is widely used in clinics, which exhibits a wide spectrum of pharmacological properties including anti-oxidative stress. It has been demonstrated that ALA could decrease markers of oxidative stress following stroke or traumatic brain damage in both human and animal studies (Packer et al., 1997, Hall et al., 2010). Administration of ALA to rodents has been also demonstrated to reduce the damage that occurs after ischemia–reperfusion injuries in the cerebral cortex (Packer et al., 1997), spinal cord (Cosar et al., 2007), peripheral nerve (Mitsui et al., 1999) and ovaries (Shaafi et al., 2011). The protective effect maybe associated with increasing activity of superoxide dismutase (SOD). Previous study showed that ALA enhanced the SIRT1 expression which leads to lipid-lowering effects in vitro and vivo (Chen et al., 2012b). Another group reported that ALA could restore age-associated impairment of brain energy metabolism through the modulation PGC-1α pathway (Jiang et al., 2013).

This study was designed to investigate the potential neuroprotective role of ALA in the mouse model of pMCAO and whether the therapeutic benefit of ALA was associated with the activation of SIRT1/PGC-1α pathway.

Section snippets

Experimental animals and drug administration

Male CD1 mice (25–30 g) were purchased from the Vital River Laboratory Animal Technology Co. Ltd, Beijing, China. The protocol was approved by the institutional animal care and use committee and the local experimental ethics committee. All mice were allowed free access to food and water under controlled conditions (12/12-h light/dark cycle with humidity of 60% ± 5%, 22 ± 3 °C).

Sixty six mice were randomly divided into three groups: the sham-operated group (Sham), in which mice received sham

ALA protects against ischemic brain injury

Neurological deficit was examined and scored on a 6-point scale at 24 h after cerebral ischemia (Fig. 1A). Mice in the Sham group had a neurological score of zero. For the mice in the pMCAO group, they remained with higher neurological deficit scores after surgery compared with the Sham group (#P < 0.05). Following MCAO, the neurological deficit scores were significantly reduced in the ALA group compared with pMCAO group (P<0.05).

Wet–dry method was used to measure brain water content. Brain edema

Discussion

Oxidative stress induced by increased intracellular ROS generation has been connected with the pathophysiology of neurotoxicity after cerebral ischemia (Crack and Taylor, 2005, Slemmer et al., 2008). Numerous antioxidants have been shown to protect neurons from the injury caused by brain ischemia and reperfusion (Warner et al., 2004, Slemmer et al., 2008, Li et al., 2013). ALA, an active free-radical scavenger, exhibits strong anti-oxidative effects (Panigrahi et al., 1996, Ozbal et al., 2012).

Conclusion

Our study showed that systemic administration of ALA alleviated neurological impairment and tissue injury in the cerebral ischemia and this effect may be through up-regulating SIRT1-dependent PGC-1α expression. ALA may be a promising protective intervention after ischemic stroke and more study is needed for clinical test in the future.

Acknowledgments

This work was funded by the National Natural Science Foundation of China (Grant no. 81371287) and Hebei Province (Grant no. C2010000564). We thank technicians Ruichun Liu and Hongran Wu for their technical assistance and Prof. Yansu Guo M.D, Ph.D. and Weisong Duan M.D, Ph.D. for providing valuable suggestions.

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