Abstract
BackgroundWe have previously identified Semaphorin 6a (Sema6A) as an upregulated gene product in a gene expression screen in cortical ischemia [1]. Semaphorin 6a was regulated during the recovery phase following ischemia in the cortex. Semaphorin 6a is a member of the superfamily of semaphorins involved in axon guidance and other functions. We hypothesized that the upregulation indicates a crucial role of this molecule in post-stroke rewiring of the brain. Here we have tested this hypothesis by overexpressing semaphorin 6a in the cortex by microinjection of a modified AAV2-virus. A circumscribed cortical infarct was induced, and the recovery of rats monitored for up to 4 weeks using a well-established test battery (accelerated rotarod training paradigm, cylinder test, adhesive tape removal). We observed a significant improvement in post-ischemic recovery of animals injected with the semaphorin 6a virus versus animals treated with a control virus. We conclude that semaphorin 6a overexpressed in the cortex enhances recovery after cerebral ischemia. Semaphorin 6a may represent a novel therapeutic candidate for the treatment of chronic stroke.
Highlights
Stroke is a major health problem in industrialized societies
Axonal pathfinding is an integral prerequisite for rewiring neuronal networks that adapt to changed functional requirements
The most well-known family of proteins involved in axonal pathfinding are the semaphorins, that fall into eight classes of membraneous or secreted proteins sharing a 500 amino acid socalled sema domain, and guide growth cones by attraction or repulsion
Summary
Stroke is a major health problem in industrialized societies. Despite numerous attempts at developing acute stroke therapies aimed at minimizing acute infarct development, the only approved therapy so far is recombinant tissue plasminogen activator (rtPA). Mechanisms that contribute to this plasticity are remapping and expansion of cortical areas to neighboring regions of functional motor cortex areas after injury [2,3,4], and reorganization of ipsilateral cortical regions distant from the injury [5]. The correlates of these plastic changes are changes in neuronal networks, mediated by the generation of new neurons (neurogenesis) [6,7], changes in dendritic and synaptic morphology [8], and changes in long-distance connectivity, requiring axonal outgrowth and pathfinding. Semaphorin 6a may represent a novel therapeutic candidate for the treatment of chronic stroke
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