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

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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.

Article Information

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.

© AANS, except where prohibited by US copyright law.

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Figures

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    Bar graphs and photomicrographs showing the density of BrdU-positive cells in the hippocampus. The left column (a, d, and g) shows the ipsilateral hemisphere and the center column (b, e, and h) shows the contralateral hemisphere. *p < 0.05 compared with the sham-injured control group; ϕp < 0.05 compared with the TBI plus saline group. The photomicrographs show BrdU-positive cells (arrows) in DG from the sham (c), TBI (f), and DETA/NONOate-treated (i) groups 14 days after TBI. Original magnification × 100.

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    a: Photomicrograph showing a representative DG from the DETA/NONOate-treated group (eight rats/group). b–e: Photomicrographs showing clusters of BrdU-positive cells in SGZ (b), hilus (c), CA1 (d), and CA3 (e) regions. CA1–3 fields represent CA1–3 of the Ammon horn. Arrows designate BrdU-positive cells. Original magnifications × 100 (a) and × 400 (b–e).

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    Bar graphs and photomicrographs showing the density of BrdU-positive cells (arrows) in the SVZ, striatum, and corpus callosum (CC). *p < 0.05 compared with the sham-injured control group; ϕp < 0.05 compared with the TBI plus saline group; #p < 0.05 compared with the density of BrdU-positive cells at 14 days after TBI and treatment. Photomicrographs showing BrdU-positive cells in the SVZ of the sham-injured (c), TBI plus saline (f), and TBI plus DETA/NONOate (i) groups (eight rats/group) 14 days after TBI; some BrdU-positive cells migrated into the striatum (i). Original magnification × 200.

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    Bar graphs and photomicrographs showing the density of BrdU-positive cells in the boundary zone and other regions of the ipsilateral cortex in the TBI plus DETA/NONOate group (a and b), the TBI plus saline group (c and d), as well as in the contralateral cortex (e) (eight rats/group). *p < 0.05 compared with the TBI plus saline group at the same time points. The photomicrographs show BrdU-positive cells in the boundary zone of the injured cortex from the TBI plus DETA/NONOate group (b) and the TBI plus saline group (d) 14 days after TBI. Original magnification × 200. BIC = boundary zone of injured cortex; ORC = other region of cortex.

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    Photomicrographs showing double immunofluorescence staining in which the representative BrdU-positive cells (a, d, and g) were colabeled with Hu (b) and GFAP (e) in the boundary zone of the injured cortex and MBP (h) in the striatum 42 days after TBI and DETA/NONOate treatment (eight rats/group). The right panels show the merged images and the arrows indicate typical BrdU-positive cells expressing Hu (c), GFAP (f), and MBP (i). Original magnifications × 200 (a–f) and × 100 (g–i).

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    Plots showing the mNSS (a) and the Corner Test scores (b) at the different time points (mean ± standard deviation). *p < 0.05 compared with the TBI plus saline group. DETA designates the TBI plus DETA/NONOate group; saline refers to the TBI plus saline group; and sham to the sham-injured group.

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