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Multiple Factors from Bradykinin-Challenged Astrocytes Contribute to the Neuronal Apoptosis: Involvement of Astroglial ROS, MMP-9, and HO-1/CO System

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Abstract

Bradykinin (BK) has been shown to induce the expression of several inflammatory mediators, including reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), in brain astrocytes. These mediators may contribute to neuronal dysfunction and death in various neurological disorders. However, the effects of multiple inflammatory mediators released from BK-challenged astrocytes on neuronal cells remain unclear. Here, we found that multiple factors were released from brain astrocytes (RBA-1) exposed to BK in the conditioned culture media (BK-CM), including ROS, MMP-9, and heme oxygenase-1 (HO-1)/carbon monoxide (CO), leading to neuronal cell (SK-N-SH) death. Exposure of SK-N-SH cells to BK-CM or H2O2 reduced cell viability and induced cell apoptosis which were attenuated by N-acetyl cysteine, indicating a role of ROS in these responses. The effect of BK-CM on cell viability and cell apoptosis was also reversed by immunoprecipitation of BK-CM with anti-MMP-9 antibody (MMP-9-IP-CM) or MMP2/9 inhibitor, suggesting the involvement of MMP-9 in BK-CM-mediated responses. Astroglial HO-1/CO in BK-CM induced cell apoptosis and reduced cell viability which was reversed by hemoglobin. Consistently, the involvement of CO in these cellular responses was revealed by incubation with a CO donor CO-RM2 which was reversed by hemoglobin. The role of HO-1 in BK-CM-induced responses was confirmed by overexpression of HO-1 in SK-N-SH infected with Adv-HO-1. BK-CM-induced cell apoptosis was due to the activation of caspase-3 and cleavage of PARP. Together, we demonstrate that BK-induced several neurotoxic factors, including ROS, MMP-9, and CO released from astrocytes, may induce neuronal death through a caspase-3-dependent apoptotic pathway.

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Acknowledgments

This work was supported by the Ministry of Education, Taiwan, Grant number: EMRPD1B0311 and EMRPD1B0321; National Science Council, Taiwan, Grant number: NSC101-2321-B-182-013, NSC101-2320-B-182-039-MY3, NSC98-2320-B-182-004-MY3, NSC98-2314-B-182-021-MY3, NSC99-2321-B182-003, and NSC98-2320-B-255-001-MY3; Chang Gung Medical Research Foundation, Grant number: CMRPD180373, CMRPG391033, CMRPG3B1091, CMRPD1B0381, CMRPF1A0061, and CMRPF1A0062.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

    Chuen-Mao Yang, Ruey-Horng Shih, Pei-Ling Chi, Shin-Ei Cheng & Li-Der Hsiao

  2. Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan, Taiwan

    Hsi-Lung Hsieh

  3. Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan

    Chih-Chung Lin

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  1. Chuen-Mao Yang
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Correspondence to Chuen-Mao Yang.

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Yang, CM., Hsieh, HL., Lin, CC. et al. Multiple Factors from Bradykinin-Challenged Astrocytes Contribute to the Neuronal Apoptosis: Involvement of Astroglial ROS, MMP-9, and HO-1/CO System. Mol Neurobiol 47, 1020–1033 (2013). https://doi.org/10.1007/s12035-013-8402-1

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