Enriched environment promotes neuroplasticity by regulating the ALK5/Smad2/3/Gadd45β signaling pathway in rats with cerebral ischemia/reperfusion injury

Abstract

AbstractBackground/AimsEnriched environment (EE) has been shown to modulate neuroplasticity in neurodegenerative diseases, but its role and mechanisms in ischemic stroke remain unclear. Our previous findings revealed that EE can promote cerebral activin receptor-like kinase 5 (ALK5) expression after cerebral ischemia/reperfusion (I/R). It was found that ALK5 might play a role in neuroplasticity through the modulation of Smad2/3/Growth Arrest DNA Damage 45 β (Gadd45β). Therefore, the present study aimed to explore the role of EE on neuroplasticity after cerebral ischemia/reperfusion and its mechanisms.MethodsThe middle cerebral artery occlusion/reperfusion (MCAO/R) method was employed to establish a rat model of cerebral ischemia/reperfusion injury. The role of ALK5 was determined by intracerebral stereotactic injection of adeno-associated virus (AAV) to inhibit the expression of ALK5. The respective effects of EE treatment with or without ALK5 knockdown on ALK5/Smad2/3/Gadd45β expression, infarct volume, newborn neurons, dendritic complexity and regenerated nerve fibers in rats were observed.ResultsCerebral I/R injury induced an increase in ALK5 expression, Smad2/3 phosphorylation ratio, and Gadd45β expression for up to 14 days. EE treatment further enhanced the expression of these molecules, which was reversed by ALK5 knockdown. The protective effect of EE treatment on brain infarct volume, neurological function, newborn neurons, dendritic complexity, and nerve fiber regeneration following I/R injury were counteracted by the AAV-ALK5-induced knockdown of ALK5.ConclusionEE treatment can enhance neuroplasticity following cerebral ischemia/reperfusion injury, which was mediated by the regulation of ALK5/Smad2/3/Gadd45β signaling pathway.