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Luteolin Protects Against CIRI, Potentially via Regulation of the SIRT3/AMPK/mTOR Signaling Pathway

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Abstract

Mitochondrial abnormalities accelerate the progression of ischemic brain damage. Sirtuin 3 (SIRT3) is mainly found in mitochondria and affects almost all major aspects of mitochondrial function. Luteolin, a flavonoid with diverse biological properties, including antioxidant activity, inhibition of cell apoptosis and regulation of autophagy. It also modulates the activity of AMP activated kinase and/or sirtuin 1 (SIRT 1) by regulating the expression of sirtuins. We investigated the protective effects of luteolin on cerebral ischemia-reperfusion. It was found through experiments that luteolin reduced the infarcted area of MCAO rat model, and based on the experimental results, it was inferred that luteolin affected the AMPK, mTOR and SIRT3 pathways, thereby protecting brain cells. As expected, we found that luteolin can reduce the neurological function score, the degree of cerebral edema, the cerebral infarction volume, alleviate morphological changes in the cortex and hippocampus, increase neuron survival and decrease the number of apoptotic neurons. At the same time, luteolin significantly reduced the number of GFAP and Iba-1 positive glial cells in the hippocampus while enhanced the scavenging of oxygen free radicals and the activity of SOD in mitochondria. Addtionally, it can also enhance antioxidant capacity via the reversal of mitochondrial swelling and the mitochondrial transmembrane potential. Moreover, luteolin can increase SIRT3-targeted expression in mitochondria, decrease the phosphorylation of AMPK, and increase phosphor-mTOR (p-mTOR) levels, which may have occurred specifically through activation of the SIRT3/AMPK/mTOR pathway. We speculate that luteolin reduces the pathological progression of CIRI by increasing SIRT3 expression and enhancing mitochondrial function. Therefore, the results indicate that luteolin can increase the transduction of SIRT3, providing a potential mechanism for neuroprotective effects in patients with cerebral ischemia.

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Funding

This project is supported by the Jilin Province Development and Reform Commission Fund 2019C050-3

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Authors and Affiliations

  1. Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People’s Republic of China

    Shuwen Liu, Yu Su, Bixi Sun, Rubin Hao, Siqi Pan, Xiaoshu Gao, Xinyue Dong, Ahmed Mohammed Ismail & Bing Han

  2. Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China

    Shuwen Liu & Rubin Hao

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  1. Shuwen Liu
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  2. Yu Su
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Correspondence to Bing Han.

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Liu, S., Su, Y., Sun, B. et al. Luteolin Protects Against CIRI, Potentially via Regulation of the SIRT3/AMPK/mTOR Signaling Pathway. Neurochem Res 45, 2499–2515 (2020). https://doi.org/10.1007/s11064-020-03108-w

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