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Inhibition of Complement Drives Increase in Early Growth Response Proteins and Neuroprotection Mediated by Salidroside After Cerebral Ischemia

Abstract

Salidroside is neuroprotective across a wide therapeutic time-window after cerebral ischemia-reperfusion injury (IRI). Here, we investigated the role of complement in mediating effects of salidroside after cerebral IRI in rats. Rats were administrated with vehicle or salidroside 50 mg/kg, given daily for either 24 or 48 h, after middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 1 h. Levels of proteins in ischemic brain were measured by immunofluorescence and western blotting. We observed early increases in the deposition of immunoglobulin M, mannose-binding lectin 2, and annexin IV on cerebral endothelial cells, induction of the complement components C3 and C3a, by 24 h after IRI, and a later significant increase in the complement component C1q by 48 h. Salidroside prevented these changes. The neuroplasticity-related early growth response proteins Egr1, Egr2, and Egr4 and activity-regulated cytoskeleton-associated protein increased transiently in the first 6 h after IRI but then decreased below baseline by 48 h after IRI. Neither salidroside nor a C3a receptor antagonist (C3aRA) affected these proteins 24 h after IRI, but both reversed their later decreases to similar and non-additive extents. Salidroside and C3aRA increased NeuN in a non-additive manner after IRI. Our results suggest that salidroside exerts neuroprotection by reducing early activation of the lectin pathway on the cerebral endothelium and inhibiting the gradual activation of the classical pathway after cerebral IRI. This prolonged neuroprotection may depend, at least in part, on increased expression of neuroplasticity-related genes driven by reduced complement activation.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Projects 81473382 and 81603323), the Department of Technology and Science of Fujian Province (Projects 2014Y4004, 2015J01328, and 2015J01685), the Collaborative Innovation Center for Rehabilitation Technology of Fujian University of Traditional Chinese Medicine (TCM), and the Rehabilitation Research of State Administration of TCM.

The authors would like to thank the staff in the Animal Center of the Fujian University of TCM for their technical supports.

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Correspondence to Guizhu Hong.

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No competing financial interests are associated with this paper.

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Wenfang Lai and XiuLi Xie contributed equally to this work.

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Lai, W., Xie, X., Zhang, X. et al. Inhibition of Complement Drives Increase in Early Growth Response Proteins and Neuroprotection Mediated by Salidroside After Cerebral Ischemia. Inflammation 41, 449–463 (2018). https://doi.org/10.1007/s10753-017-0701-7

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KEY WORDS

  • Brain ischemia
  • Complement
  • Neuroprotection
  • Salidroside