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Original Contribution

Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat

Keren Zhou, Budbazar Enkhjargal, Zhiyi Xie, Chengmei Sun, Lingyun Wu, Jay Malaguit, Sheng Chen, Jiping Tang, Jianmin Zhang, John H. Zhang
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https://doi.org/10.1161/STROKEAHA.117.018593
Stroke. 2018;49:175-183
Originally published December 22, 2017
Keren Zhou
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Budbazar Enkhjargal
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Zhiyi Xie
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Chengmei Sun
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Lingyun Wu
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Jay Malaguit
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Sheng Chen
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Jiping Tang
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Jianmin Zhang
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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John H. Zhang
From the Department of Neurosurgery, Second Affiliated Hospital, School of Medicine (K.Z., S.C., J.Z.), Brain research institute (K.Z., S.C., J.Z.), and Collaborative Innovation Center for Brain Science (K.Z., S.C., J.Z.), Zhejiang University, Hangzhou, China; and Department of Physiology and Pharmacology, Loma Linda University, CA (K.Z., B.E., Z.X.,C.S., L.W., J.M., J.T., J.H.Z.).
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Abstract

Background and Purpose—The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway.

Methods—SAH was induced by endovascular perforation in male Sprague–Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKIIα (calcium/calmodulin-dependent protein kinase II α) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed.

Results—DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIα and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIα, p-TAK1 (phosphorylated transforming growth factor-β-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIα small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH.

Conclusions—DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.

  • calcium-calmodulin-dependent protein kinase type 2
  • dihydrolipoic acid
  • inflammasomes
  • lysosomal-associated membrane protein 1
  • subarachnoid hemorrhage
  • Received June 29, 2017.
  • Revision received October 28, 2017.
  • Accepted November 3, 2017.
  • © 2017 American Heart Association, Inc.
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    Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat
    Keren Zhou, Budbazar Enkhjargal, Zhiyi Xie, Chengmei Sun, Lingyun Wu, Jay Malaguit, Sheng Chen, Jiping Tang, Jianmin Zhang and John H. Zhang
    Stroke. 2018;49:175-183, originally published December 22, 2017
    https://doi.org/10.1161/STROKEAHA.117.018593

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    Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat
    Keren Zhou, Budbazar Enkhjargal, Zhiyi Xie, Chengmei Sun, Lingyun Wu, Jay Malaguit, Sheng Chen, Jiping Tang, Jianmin Zhang and John H. Zhang
    Stroke. 2018;49:175-183, originally published December 22, 2017
    https://doi.org/10.1161/STROKEAHA.117.018593
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