Abstract
Using a model of middle cerebral artery occlusion (MCAO), we have previously demonstrated that treadmill exercise promotes angiogenesis in the ischemic penumbra through caveolin-1/VEGF signaling pathways. However, the function of caveolin-1/VEGF signaling in neurogenesis after MCAO has not been determined. In this study, we aimed to investigate the potential of treadmill exercise to promote neurogenesis after MCAO and whether caveolin-1/VEGF signaling pathways are involved. After MCAO, rats were subjected to a program of treadmill exercise. Daidzein (a specific inhibitor of caveolin-1 protein expression, 0.4 mg/kg) was used to confirm the effect of caveolin-1/VEGF signaling on exercise-mediated neurogenesis. We found that the total protein expression of both caveolin-1 and VEGF was increased by exercise and consistent with the improved neurological recovery, decreased infarct volumes and increased 5-bromo-2′-deoxyuridine (BrdU) in the ipsilateral Subventricular zone (SVZ), as well as increased numbers of BrdU/DCX and BrdU/Neun-positive cells in the peri-infarct region. Furthermore, we observed that the treadmill exercise-induced increased VEGF expression, improved neurological recovery, decreased infarct volumes, increased BrdU/DCX and BrdU/Neun-positive cells were significantly inhibited by the caveolin-1 inhibitor. Our results indicate that treadmill exercise improves neurological recovery in ischemic rats, possibly by enhancement of SVZ-derived neural stem cell (NSC) proliferation, migration and differentiation in the penumbra. Moreover, caveolin-1/VEGF signaling is involved in exercise-mediated NSC migration and neuronal differentiation.
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Abbreviations
- MCAO:
-
Middle cerebral artery occlusion
- S:
-
Sham-operated
- M:
-
Model
- EM:
-
Exercise and model
- IM:
-
Inhibitor and model
- IEM:
-
Inhibitor, exercise, and model
- SVZ:
-
Subventricular zone
- SGZ:
-
The subgranular zone
- NSC:
-
Neural stem cell
- NPC:
-
Neural progenitor cell
- VEGF:
-
Vascular endothelial growth factor
- DCX:
-
Doublecortin
- Neun:
-
Neuron-specific nuclear protein
- BrdU:
-
5-Bromo-2′-deoxyuridine
- EGF:
-
Epidermal growth factor
- bFGF:
-
Basic fibroblast growth factor
- BDNF:
-
Brain-derived neurotrophic factor
- VEGFR2:
-
Vascular endothelial growth factor receptor 2
- NMDAR:
-
N-Methyl-d-aspartate receptor
- SFK:
-
Src family kinase
- ERK:
-
Extracellular signal-regulated kinase
- eNOS:
-
Endothelial nitric oxide synthase
- GPCRs:
-
G protein coupled receptors
- PLC:
-
Phosphoinositide-specific phospholipase C
- Akt:
-
Protein kinase B
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Acknowledgments
This study was supported partially by the Natural Science Foundation of Zhejiang Province Project (No. Y12H170002) and the Science Technology Bureau of Wenzhou funded project (No. Y20140677). We also appreciate the great technical assistance provided by the Experimental Animal Center of Wenzhou Medical University and the Laboratory Center of the Second Affiliated Hospital of Wenzhou Medical University & Yuying Children’s Hospital.
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Zhao, Y., Pang, Q., Liu, M. et al. Treadmill Exercise Promotes Neurogenesis in Ischemic Rat Brains via Caveolin-1/VEGF Signaling Pathways. Neurochem Res 42, 389–397 (2017). https://doi.org/10.1007/s11064-016-2081-z
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DOI: https://doi.org/10.1007/s11064-016-2081-z