Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury.
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.
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Yoon Kyung
YK
Choi
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Takakuni
T
Maki
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Emiri T
ET
Mandeville
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
Seong-Ho
0000-0001-5419-5761
SH
Koh
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Kazuhide
K
Hayakawa
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Ken
K
Arai
Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea.
Young-Myeong
YM
Kim
Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Michael J
MJ
Whalen
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Changhong
C
Xing
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Xiaoying
X
Wang
SNU-Harvard NeuroVascular Protection Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Kyu-Won
KW
Kim
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.|Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Eng H
EH
Lo
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000070642:Brain Injuries, Traumatic / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D000066449:Human Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D020286:Pericytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D001973:Bromodeoxyuridine
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