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Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

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Abstract

Astrocytes are the most numerous cells in the central nervous system with a range of homeostatic and regulatory functions. Under normal conditions as well as after ischemia, astrocytes promote neuronal survival. We have previously reported that the complement-derived peptide C3a stimulates neuronal differentiation of neural progenitor cells and protects the immature brain tissue against hypoxic-ischemic injury. Here, we studied the effects of C3a on the response of mouse cortical astrocytes to ischemia. We have found that chemical ischemia, induced by combined inhibition of oxidative phosphorylation and glycolysis, upregulates the expression of C3a receptor in cultured primary astrocytes. C3a treatment protected wild-type but not C3a receptor-deficient astrocytes from cell death induced by chemical ischemia or oxygen-glucose deprivation by reducing ERK signaling and caspase-3 activation. C3a attenuated ischemia-induced upregulation of glial fibrillary acidic protein; however, the protective effects of C3a were not dependent on the presence of the astrocyte intermediate filament system. Pre-treatment of astrocytes with C3a during recovery abrogated the ischemia-induced neuroprotective phenotype of astrocytes. Jointly, these results provide the first evidence that the complement peptide C3a modulates the response of astrocytes to ischemia and increases their ability to cope with ischemic stress.

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Acknowledgments

This work was supported by the Swedish Medical Research Council (project 11548 and 20116), AFA Research Foundation, ALF Göteborg (project 11392 and 142821), Sten A. Olsson Foundation for Research and Culture, Söderberg Foundations, Hjärnfonden, Hagströmer’s Foundation Millennium, the Swedish Stroke Foundation, the Free Mason Foundation, Amlöv’s Foundation, E. Jacobson’s Donation Fund, the EU FP 7 Program TargetBraIn (279017), and NanoNet COST Action (BM1002).

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Authors and Affiliations

  1. Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 440, 405 30, Gothenburg, Sweden

    Noriko Shinjyo, Yolanda de Pablo, Milos Pekny & Marcela Pekna

  2. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia

    Milos Pekny & Marcela Pekna

  3. University of Newcastle, Newcastle, NSW, Australia

    Milos Pekny & Marcela Pekna

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  1. Noriko Shinjyo
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  2. Yolanda de Pablo
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  3. Milos Pekny
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  4. Marcela Pekna
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Correspondence to Milos Pekny or Marcela Pekna.

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Shinjyo, N., de Pablo, Y., Pekny, M. et al. Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress. Mol Neurobiol 53, 3076–3087 (2016). https://doi.org/10.1007/s12035-015-9204-4

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