Abstract
Ischemic stroke is a leading cause of adult disability, including cognitive impairment. Our laboratory has previously shown that treatment with function-blocking antibodies against the neurite growth inhibitory protein Nogo-A promotes functional recovery after stroke in adult and aged rats, including enhancing spatial memory performance, for which the hippocampus is critically important. Since spatial memory has been linked to hippocampal neurogenesis, we investigated whether anti-Nogo-A treatment increases hippocampal neurogenesis after stroke. Adult rats were subject to permanent middle cerebral artery occlusion followed 1 week later by 2 weeks of antibody treatment. Cellular proliferation in the dentate gyrus was quantified at the end of treatment, and the number of newborn neurons was determined at 8 weeks post-stroke. Treatment with both anti-Nogo-A and control antibodies stimulated the accumulation of new microglia/macrophages in the dentate granule cell layer, but neither treatment increased cellular proliferation or the number of newborn neurons above stroke-only levels. These results suggest that anti-Nogo-A immunotherapy does not increase post-stroke hippocampal neurogenesis.
Highlights
Cognitive impairment is a recognized sequela of ischemic stroke (Gottesman and Hillis, 2010)
Our results showed that while infusion of both anti-NogoA and control antibodies led to the accumulation of new microglia/macrophages in the hippocampus, Nogo-A neutralization did not affect the number of newborn neurons in the dentate gyrus after stroke
Enhanced neurogenesis is unlikely to contribute to the improvement in spatial memory that we previously reported after stroke and anti-Nogo-A immunotherapy
Summary
Cognitive impairment is a recognized sequela of ischemic stroke (Gottesman and Hillis, 2010). We and others have previously demonstrated that antiNogo-A immunotherapy stimulates dendritic and axonal remodeling and increases dendritic spine density in the contralesional sensorimotor cortex after stroke (Papadopoulos et al, 2002, 2006; Wiessner et al, 2003; Seymour et al, 2005; Tsai et al, 2007, 2011; Lindau et al, 2014) These neuroplastic changes may underlie the sensorimotor recovery seen in anti-Nogo-A treated animals (Papadopoulos et al, 2002, 2006; Wiessner et al, 2003; Seymour et al, 2005; Tsai et al, 2007, 2011; Lindau et al, 2014; reviewed by Kumar and Moon, 2013), as silencing of newly sprouted axonal connections ablates the sensorimotor recovery promoted by anti-Nogo-A treatment (Wahl et al, 2014). No changes in dendritic complexity or spine density were found in antiNogo-A-treated animals in pyramidal neurons of CA1 or CA3 or in dentate granule cells, despite spatial memory improvement, suggesting an alternate mechanism of efficacy (Gillani et al, 2010).
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