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

Nat Med. 2016 Nov;22(11):1335-1341. doi: 10.1038/nm.4188. Epub 2016 Sep 26.


At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator. 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.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Blotting, Western
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Injuries, Traumatic / metabolism*
  • Bromodeoxyuridine / metabolism
  • Carbon Monoxide / metabolism*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Immunohistochemistry
  • In Vitro Techniques
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neurogenesis / drug effects*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / genetics
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism
  • Organometallic Compounds / pharmacology*
  • Pericytes / cytology
  • Pericytes / drug effects*
  • Pericytes / metabolism
  • Reactive Oxygen Species / metabolism


  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nerve Tissue Proteins
  • NeuN protein, mouse
  • Nuclear Proteins
  • Organometallic Compounds
  • Reactive Oxygen Species
  • tricarbonylchloro(glycinato)ruthenium(II)
  • Carbon Monoxide
  • NOS1 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Bromodeoxyuridine