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The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron

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Abstract

α-Lipoic acid-plus (LAP), an amine derivative of α-lipoic acid (LA), could protect cells against oxidant challenges via chelating intralysosomal iron. However, the application of LAP in experimental subarachnoid hemorrhage (SAH) is still not well known. This study was designed to evaluate the potential neuroprotection of LAP on the early brain injury (EBI) and the underlying mechanisms in a rat model of SAH. The SAH models were induced in Sprague–Dawley rats. LA and LAP were oral administration and lasted for 72 h once a day. The brain tissue samples were obtained for assay at 72 h after SAH. In experiment 1, we found that lysosome amounts in neurons decreased significantly in SAH group, and LAP (100 mg/kg) could stabilize lysosomal membrane markedly based on lysosomal-associated membrane protein-1 (LAMP-1) expression in neurons by immunofluorescence. Hence, the LAP dosages of 100 and 150 mg/kg were applied in experiment 2. Firstly, Western blot analysis showed that the protein levels of cathepsin B/D, caspase-3, Bax, ferritin, and heme-oxygenase-1 (HO-1) markedly increased after SAH, which were further confirmed by double immunofluorescence staining and reversed by LA and LAP treatments. In addition, LA and LAP also reduced oxidative stress and iron deposition in brain tissue. Furthermore, LA and LAP significantly ameliorated brain edema, blood–brain barrier injury, cortical apoptosis, and neurological behavior impairment induced by SAH. Finally, it is noteworthy that LAP exerted more significant effects than LA on these parameters as described above. LAP probably exerted neuroprotective effects via targeting lysosomes and chelating intralysosomal iron in EBI post-SAH in rats.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81171105, 81271300, and 81371279), Jiangsu Province’s Outstanding Medical Academic Leader program (No. LJ201139), the National Key Technology R&D program for the 12th Five-Year Plan of the People’s Republic of China (2011BAI08B05, 2011BAI08B06, and 2014BAZ04810), and the Scientific Department of Jiangsu Province (No. BL2014045) and Suzhou Government (Nos. LCZX201301, SZS201413, and SYS201332).

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, People’s Republic of China

    Yang Wang, Anju Gao, Xiang Xu, Baoqi Dang, Wanchun You, Haiying Li, Zhengquan Yu & Gang Chen

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  1. Yang Wang
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Correspondence to Zhengquan Yu or Gang Chen.

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Yang Wang and Anju Gao equally contribute to this work.

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Wang, Y., Gao, A., Xu, X. et al. The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron. Mol Neurobiol 52, 64–77 (2015). https://doi.org/10.1007/s12035-014-8846-y

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