Upregulation of neurogenesis and reduction in functional deficits following administration of DETA/NONOate, a nitric oxide donor, after traumatic brain injury in rats

Dunyue Lu M.D., Ph.D. 1 , Asim Mahmood M.D. 1 , Ruilan Zhang M.D. 1 , Yi Li M.D. 1 , and Michael Chopp Ph.D. 1
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  • 1 Departments of Neurosurgery and Neurology, Henry Ford Health Sciences Center, Detroit; and Department of Physics, Oakland University, Rochester, Michigan
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Object. Neurogenesis, which is upregulated by neural injury in the adult mammalian brain, may be involved in the repair of the injured brain and functional recovery. Therefore, the authors sought to identify agents that can enhance neurogenesis after brain injury, and they report that (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NONOate), a nitric oxide donor, upregulates neurogenesis and reduces functional deficits after traumatic brain injury (TBI) in rats.

Methods. The agent DETA/NONOate (0.4 mg/kg) was injected intraperitoneally into 16 rats daily for 7 days, starting 1 day after TBI induced by controlled cortical impact. Bromodeoxyuridine (100 mg/kg) was also injected intraperitoneally daily for 14 days after TBI to label the newly generated cells in the brain. A neurological functional evaluation was performed in all rats and the animals were killed at 14 or 42 days postinjury. Immunohistochemical staining was used to identify proliferating cells.

Conclusions. Compared with control rats, the proliferation, survival, migration and differentiation of neural progenitor cells were all significantly enhanced in the hippocampus, subventricular zone, striatum, corpus callosum, and the boundary zone of the injured cortex, as well as in the contralateral hemisphere in rats with TBI that received DETA/NONOate treatment. Neurological functional outcomes in the DETA/NONOate-treated group were also significantly improved compared with the untreated group. These data indicate that DETA/NONOate may be useful in the treatment of TBI.

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Contributor Notes

Address reprint requests to: Michael Chopp, Ph.D., Neurology Department, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. email: chopp@neuro.hfh.edu.
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