Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury

Abstract

At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator1,2. Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2′-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: CORM-3 treatment decreases pericyte damage after TBI.
Figure 2: Treatment with CORM-3 or PBN ameliorates vascular dysfunction after TBI.
Figure 3: CORM-3 rescues functional deficits after TBI.
Figure 4: CORM-3 enhances NOS-mediated neurogenesis via cross-talk between pericytes and NSCs.

References

  1. Motterlini, R. & Otterbein, L.E. The therapeutic potential of carbon monoxide. Nat. Rev. Drug Discov. 9, 728–743 (2010).

    Article  CAS  Google Scholar 

  2. Verma, A., Hirsch, D.J., Glatt, C.E., Ronnett, G.V. & Snyder, S.H. Carbon monoxide: a putative neural messenger. Science 259, 381–384 (1993).

    Article  CAS  Google Scholar 

  3. Loane, D.J. & Faden, A.I. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol. Sci. 31, 596–604 (2010).

    Article  CAS  Google Scholar 

  4. Xiong, Y., Mahmood, A. & Chopp, M. Animal models of traumatic brain injury. Nat. Rev. Neurosci. 14, 128–142 (2013).

    Article  CAS  Google Scholar 

  5. Xiong, Y., Mahmood, A. & Chopp, M. Emerging treatments for traumatic brain injury. Expert Opin. Emerg. Drugs 14, 67–84 (2009).

    Article  CAS  Google Scholar 

  6. Wang, G. et al. HDAC inhibition prevents white matter injury by modulating microglia–macrophage polarization through the GSK-3β–PTEN–Akt axis. Proc. Natl. Acad. Sci. USA 112, 2853–2858 (2015).

    Article  CAS  Google Scholar 

  7. Hu, X. et al. Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles. Prog. Neurobiol. 119-120, 60–84 (2014).

    Article  CAS  Google Scholar 

  8. Bell, R.D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).

    Article  CAS  Google Scholar 

  9. Bell, R.D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

    Article  CAS  Google Scholar 

  10. Goldman, S.A. & Chen, Z. Perivascular instruction of cell genesis and fate in the adult brain. Nat. Neurosci. 14, 1382–1389 (2011).

    Article  CAS  Google Scholar 

  11. Chen, J. et al. The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance. Dev. Biol. 269, 165–182 (2004).

    Article  CAS  Google Scholar 

  12. Yemisci, M. et al. Pericyte contraction induced by oxidative–nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031–1037 (2009).

    Article  CAS  Google Scholar 

  13. Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405 (2011).

    Article  CAS  Google Scholar 

  14. Lo, E.H., Lok, J., Ning, M. & Whalen, M. (eds.) Vascular Mechanisms in CNS Trauma (Springer, New York, 2014).

  15. Xing, C. & Lo, E.H. Help-me signaling: non-cell-autonomous mechanisms of neuroprotection and neurorecovery. Prog. Neurobiol. S0301-0082(15)30024-1 (2016).

  16. Fujita, T. et al. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by de-repression of fibrinolysis. Nat. Med. 7, 598–604 (2001).

    Article  CAS  Google Scholar 

  17. Lo, E.H. Degeneration and repair in central nervous system disease. Nat. Med. 16, 1205–1209 (2010).

    Article  CAS  Google Scholar 

  18. National Research Council. Guide for the Care and Use of Laboratory Animals 8th edn. (The National Academies Press, 2011).

Download references

Acknowledgements

This work was supported in part by grants from the US National Institutes of Health (K.H., K.A., M.J.W., C.X., X.W. and E.H.L.), the Rappaport Foundation (E.H.L.), the Research Abroad grant from the National Research Foundation of Korea (Y.K.C., S.-H.K., Y.-M.K. and K.-W.K.) and the Global Research Laboratory Program of Korea (K.-W.K.). The vector expressing the HIF-1α double mutant was kindly provided by G.L. Semenza (Johns Hopkins University School of Medicine).

Author information

Authors and Affiliations

Authors

Contributions

Y.K.C. and E.H.L. designed experiments and wrote the manuscript; Y.K.C., T.M., E.T.M., C.X., S.-H.K., K.H. and X.W. performed experiments; K.A., Y.-M.K., M.J.W., X.W. and K.-W.K. analyzed and critically discussed the data; and E.H.L. supervised the project.

Corresponding authors

Correspondence to Yoon Kyung Choi or Eng H Lo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 4214 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Choi, Y., Maki, T., Mandeville, E. et al. Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury. Nat Med 22, 1335–1341 (2016). https://doi.org/10.1038/nm.4188

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4188

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing