Abstract 2976: Sildenafil Enhances Neurogenesis And Oligodendrogenesis In The Ischemic Brain Of Aged Mouse
Sildenafil enhances neurogenesis and oligodendrogenesis in the ischemic brain of aged mouse Rui Lan Zhang1, Michael Chopp1,2 Cynthia Roberts1, Min Wei1, Xinli Wang1, Xianshuang Liu1, Zheng Gang Zhang1 Departments of 1Neurology and Henry Ford Hospital, Detroit, MI, USA 2Oakland University, Physics Department, Rochester, MI, USA.
Background and Purpose: Nestin lineage neural progenitor cells contribute to neurogenesis in adult rodent brain under non-ischemic and ischemic conditions. The present study investigated the effect of sildenafil, a potent phosphodiesterase 5 (PDE5) inhibitor, on nestin lineage neural progenitor cells in the aged mouse after stroke.
Methods: Male Nestin-CreERT2;R26R-stop-YFP mice at age 16 months were used. Tamoxifen was daily injected for 5 days to activate Cre/loxP system under control of the nestin promoter, leading to permanent YFP labeling of nestin lineage cells. These mice were subjected to permanent middle cerebral artery occlusion (MCAo) 14 days after the last tamoxifen injection. Sildenafil at 10mg/kg (n=11) or saline (n=10) was aadministered daily for 7 days starting 1 day after MCAo. All mice were sacrificed 30 days after MCAo. The number of nestin lineage cells and their fate were analyzed using immunohistochemistry staining.
Results: Double immunofluorescent staining confirmed YFP positive cells were nestin positive. Unbiased stereological analysis revealed that sildenafil treatment significantly increased (p<0.05) the number of nestin linage cells in the ischemic subventricular zone (SVZ, 803 ± 28 vs 657 ± 41 in saline), striatum (3739 ± 162 vs 3029 ± 144 in saline), and corpus callosum (2957 ± 86 vs 2578 ± 117 in saline). Phenotype analysis showed that sildenafil substantially augmented the number of nestin lineage neuroblasts identified by doublecortin positive cells (19.4 ± 1.6 % vs 12.9 ± 1.1 % in saline), nestin lineage mature neurons measured by NeuN (6.2 ± 0.8 % vs 3.0 ± 0.6 %) and calbindin (10.8 ± 0.9 vs 7.2 ± 1.1) positive cells in the ischemic striatum. Sildenafil also significantly (p<0.05) increased the number of nestin lineage oligodendrocytes measured by 2’, 3’-cyclic nucleotide, 3’-phosphodiesterase (CNPase) positive cells in ischemic striatum (21.3 ± 1.2 vs 19.9 ± 1.4 in saline) and corpus callosum (18.9 ± 1.4 vs 14.4 ± 1.3 in saline).
Conclusion: Our data demonstrate that sildenafil enhances neurogenesis and oligodendrogenesis in the ischemic brain of the aged mouse, which could contribute sildenafil-improved neurological outcome after stroke which we have demonstrated.
- © 2012 by American Heart Association, Inc.