Abstract
This study aimed to investigate the effects of enriched environment (EE) on promoting angiogenesis and neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in seven day-old CD-1® mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At six weeks of age, the mice were randomly assigned to either EE or standard cages (SC) for two months. Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. In order to identify angiogenic growth factors regulated by EE, an array-based multiplex ELISA assay was used to measure the expression in frontal cortex, striatum, and cerebellum. Among the growth factors, the expression of fibroblast growth factor-2 (FGF-2) was confirmed using western blotting. Platelet endothelial cell adhesion molecule-1 (PECAM-1) and α-smooth muscle actin (α-SMA) were also evaluated using immunohistochemistry. As a result, mice exposed to EE showed significant improvements in rotarod and ladder walking performances compared to SC controls. The level of FGF-2 was significantly higher in the frontal cortex of EE mice at 8 weeks after treatment in multiplex ELISA and western blot. On the other hand, FGF-2 in the striatum significantly increased at 2 weeks after exposure to EE earlier than in the frontal cortex. Expression of activin A was similarly upregulated as FGF-2 expression pattern. Particularly, all animals treated with FGF-2 neutralizing antibody abolished the beneficial effect of EE on motor performance relative to mice not given anti-FGF-2. Immunohistochemistry showed that densities of α-SMA+ and PECAM-1+ cells in frontal cortex, striatum, and hippocampus were significantly increased following EE, suggesting the histological findings exhibit a similar pattern to the upregulation of FGF-2 in the brain. In conclusion, EE enhances endogenous angiogenesis and neurobehavioral functions mediated by upregulation of FGF-2 in chronic hypoxic-ischemic brain injury.
Highlights
Hypoxic-ischemic (HI) brain injury is a major cause of damage to fetal and neonatal brains, and results in considerable morbidity of neurological diseases with neurodevelopmental impairment such as cerebral palsy [1,2]
When we evaluated the rotarod performance in mice with no HI brain injury to know the EE-induced effect on normal condition, they promoted locomotor function 8 weeks after EE
The present study showed that the densities of Platelet endothelial cell adhesion molecule-1 (PECAM-1)+ and a-smooth muscle actin (a-SMA)+ cells in the frontal cortex and the striatum of EE mice were significantly increased after treatment, demonstrating a similar pattern to the upregulation of fibroblast growth factor-2 (FGF-2)
Summary
Hypoxic-ischemic (HI) brain injury is a major cause of damage to fetal and neonatal brains, and results in considerable morbidity of neurological diseases with neurodevelopmental impairment such as cerebral palsy [1,2]. The striatum and the cerebellum are main areas involved in maintaining motor coordination and balance. The brain areas do not function alone, but interact with the frontal cortex. Because there is a paucity of effective treatments available for adults who have chronic HI brain injury, rehabilitative exercise with exposure to enriched environment (EE) has been a traditional way as a potential treatment to elicit neurorestorative effects in the frontal cortex, striatum, and cerebellum of the brain. Exposure to EE after brain injury has been shown to provide neuroprotective effects, reducing lesion size and increasing dendritic outgrowth and the production of trophic factors [4]. The therapeutic mechanism for how exercise affects the functional outcomes of the brain has been largely unknown
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