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Neuroprotective Effects of Dehydroepiandrosterone Sulfate Through Inhibiting Expression of Matrix Metalloproteinase-9 from Bradykinin-Challenged Astroglia

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Abstract

Dehydroepiandrosterone sulfate (DHEAS), one of the most important neuroactive steroids, is produced in the adrenals and the brain. DHEAS is believed to play a critical role in modulating different forms of cellular control, including processes associated with human neural systems. Its production rate and level in serum, adrenals, and brain gradually decrease with advancing age. The decline of DHEAS level was associated with age-related neuronal dysfunction and degeneration, most probably because the steroids protect the central nervous system (CNS) neurons against neurotoxic challenges. Moreover, increasing studies show that matrix metalloproteinases (MMPs), MMP-9 especially, are upregulated by proinflammatory mediators in the CNS disorders. The increased MMP-9 as an inflammatory biomarker of several CNS disorders that may participate in the CNS inflammation and neurodegeneration. Herein, we investigate the effects of DHEAS on brain inflammation by the model we have defined of bradykinin (BK)-induced MMP-9 expression in rat brain astrocyte (RBA) and its mechanism. The results showed that DHEAS significantly reduce MMP-9 induced by BK. Pretreatment with DHEAS can inhibit BK-stimulated phosphorylation of c-Src and PYK2. Moreover, DHEAS attenuated BK-stimulated NADPH oxidase (Nox)-derived reactive oxygen species (ROS) production, suggesting that DHEAS has an antioxidative effect. We further demonstrated that DHEAS blocked activation of ERK1/2, Akt, and c-Fos/AP-1 by BK. Finally, DHEAS decreased MMP-9-related events including RBA migration and neuronal apoptosis. The results will provide new insights into the anti-inflammatory action of DHEAS, supporting that DHEAS may have a neuroprotective effect in the improvement of the CNS disorders by reducing neuroinflammation.

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Acknowledgements

This work was supported by the Ministry of Science and Technology, Taiwan; Grant number: NSC102-2320-B-255-005-MY3 and MOST106-2320-B-255-005; Chang Gung Medical Research Foundation, Grant number: CMRPF1C0193, CMRPF3D0033, CMRPF1F0131, and CMRPF1F0132. We thank Ms. Yin-Chen Chen and Shu-Ching Hsu for their technical assistance. We also thank Professor Ying-Tung Lau for his support.

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Authors and Affiliations

  1. Department of Nursing, Division of Basic Medical Sciences, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan

    Chian-Jiun Liou & Hsi-Lung Hsieh

  2. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Gui-Shan, Taoyuan, Taiwan

    Chian-Jiun Liou

  3. Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan

    Chuen-Mao Yang

  4. Stroke Center and Stroke Section, Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Tao-Yuan, Taiwan

    Tsong-Hai Lee

  5. Department of Microbiology, Soochow University, Taipei, Taiwan

    Pei-Shan Liu

  6. Department of Neurology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

    Hsi-Lung Hsieh

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  1. Chian-Jiun Liou
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Correspondence to Hsi-Lung Hsieh.

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Liou, CJ., Yang, CM., Lee, TH. et al. Neuroprotective Effects of Dehydroepiandrosterone Sulfate Through Inhibiting Expression of Matrix Metalloproteinase-9 from Bradykinin-Challenged Astroglia. Mol Neurobiol 56, 736–747 (2019). https://doi.org/10.1007/s12035-018-1125-6

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