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

I have 9 posts on carbon monoxide back to 2012 and I'm sure there has been no followup since then because we have NO leadership to go to or a strategy to update.
http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4188.html

• Yoon Kyung Choi,^{1, 2,}
• Takakuni Maki,^{1, 2,}
• Emiri T Mandeville,^{1, 2,}
• Seong-Ho Koh,^{1, 2, 3,}
• Kazuhide Hayakawa,^{1, 2,}
• Ken Arai,^{1, 2,}
• Young-Myeong Kim,^4,
• Michael J Whalen,^5,
• Changhong Xing,^{1, 2,}
• Xiaoying Wang,^{1, 2,}
• Kyu-Won Kim^6,
• & Eng H Lo^{1, 2,}

• Affiliations
• Contributions
• Corresponding authors

Journal name:

Nature Medicine

Year published:

(2016)

DOI:

doi:10.1038/nm.4188

Received

31 March 2016

Accepted

26 August 2016

Published online

26 September 2016

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At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator^{1, 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.