Impact of inhibition of erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the hippocampus on restoration of spatial learning after traumatic brain injury

Abstract

Our previous study demonstrates that delayed (initiated 24 hours post injury) erythropoietin (EPO) therapy for traumatic brain injury (TBI) significantly improves spatial learning. In this study, we investigated the impact of inhibition of EPO treatment-mediated neurogenesis on spatial learning after experimental TBI. Young male Wistar rats (318±7g) were subjected to unilateral controlled cortical impact injury. TBI rats received delayed EPO treatment (5,000 U/kg in saline) administered intraperitoneally once daily at 1, 2, and 3 days post injury and intracerebroventricular (icv) infusion of either a mitotic inhibitor cytosine-b-D-arabinofuranoside or vehicle (saline) for 14 days. Another 2 groups of TBI rats were treated intraperitoneally with saline and infused icv with either a mitotic inhibitor Ara-C or saline for 14 days. Animals receiving sham operation were infused icv with either Ara-C infusion or saline. Bromodeoxyuridine (BrdU) was administered to label dividing cells. Spatial learning was assessed using a modified Morris water maze test. Animals were sacrificed at 35 days after injury and brain sections stained for immunohistochemical analyses. As compared to the saline treatment, immunohistochemical analysis revealed that delayed EPO treatment significantly increased the number of BrdU-positive cells and new neurons co-stained with BrdU and NeuN (mature neuron marker) in the dentate gyrus in TBI rats. EPO treatment improved spatial learning after TBI. Ara-C infusion significantly abolished neurogenesis and spatial learning recovery after TBI and EPO treatment. Both EPO and Ara-C reduced the number of astrocytes and microglia/macrophages in the dentate gyrus after TBI. Our findings are highly suggestive for an important role of EPO-amplified dentate gyrus neurogenesis as one of the mechanisms underlying EPO therapeutic treatments after TBI, strongly indicating that strategies promoting endogenous neurogenesis may hold an important therapeutic potential for treatment of TBI.

The efficacy of erythropoietin in treating experimental traumatic brain injury: a systematic review of controlled trials in animal models

“…On the basis of predefined criteria, 277 studies were excluded, leaving 13 studies 2,15,25,29,43,[45][46][47][48][49][50][51][52] for systematic review. One study 2 was excluded from the meta-analysis because sample sizes were not stated, and we were unable to obtain this information from the authors.…”

“…Therefore, the meta-analysis ultimately included 11 studies. 25,29,43,[45][46][47][48][49][50][51][52] Among the included studies (Table 1), treatment outcomes were measured for 1 to 90 days after TBI. Ten studies used rats, and 3 studies used mice.…”

“…Within 10 included trials, 25,29,43,[45][46][47][48][49][50]52 there were 18 comparisons (involving 296 animals) of spatial learning and memory deficits performed using the MWM 35 days after TBI. Pooled analysis indicated that animals in the treatment groups significantly improved spatial learning performance (that is, greater percentage of time spent in the correct quadrant) compared with animals in the control groups (SMD = 3.933; 95% CI 3.355-4.512, p < 0.0001).…”

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

“…Impaired neurogenesis (Acosta et al, 2013; Esposito, Hayakawa, Maki, Arai, & Lo, 2015; Kokaia & Darsalia, 2011; Sun et al, 2013, 2016; Xia et al, 2006; Zhang et al, 2012) accompanies many neurological disorders, including stroke. Enhancement of host neurogenesis may serve as a novel therapy for stroke, which remains a significant unmet clinical need with efficacy of tissue plasminogen activator or tPA limited to 4.5 hr.…”

“…In this study, we tested in a stroke model the therapeutic effects of NSI‐189, a small molecule with enhanced neurogenic activity, which is already in clinical trial for treatment of major depression and prevention against suicide (ClinicalTrials.gov, 2016; Fava et al, 2015). While the brain exerts self‐repair acutely, over time the stroke‐induced cascade of cell death events outweighs the endogenous regenerative mechanisms (Acosta et al, 2013; Fava et al, 2015; Kokaia & Darsalia, 2011; Sun et al, 2013, 2016; Zhang et al, 2012). Thus, finding a therapeutic strategy to stimulate the brain to mount a prolonged and stable reparative machinery during the secondary cell death progression after stroke will likely afford beneficial effects.…”