The role of EphA4 in stroke recovery

Stroke is a loss of brain function due to an interruption of cerebral blood flow caused by occlusion (ischemic stroke) or hemorrhage1. It is the leading cause of adult disability and it causes one in 10 deaths worldwide2. The only effective treatments are intravenous recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy, which have narrow time windows that limit their use to only a small percentage of patients with ischemic stroke3-5. Therefore, new therapeutic strategies remain necessary. During stroke, ischemia initiates various molecular events. Due to the lack of blood flow, neurons do not get sufficient amounts of oxygen and metabolic substrates resulting in decreased energy production, excitotoxicity, accumulation of ions, mitochondrial injury and eventually neuronal apoptotic and necrotic cell death causing impaired sensory and motor functioning1,6. Although stroke damage can be devastating, many patients survive the initial event and undergo some spontaneous recovery, a process that can be enhanced by rehabilitation therapy1. Recovery involves different mechanisms including neuronal repair, neurogenesis, alterations in existing neuronal pathways, and the formation of new neuronal connections7. However, these restorative responses are limited due to the upregulation of various inhibitory molecules including myelin associated proteins, components of the glial scar and increased expression of developmental axonal guidance cues like components of the ephrin system8,9. The ephrin family consists of Eph receptors and ephrin ligands that act as growth inhibitory proteins10,11. One receptor, EphA4, is of specific interest since we have found increased EphA4 protein levels in the ipsilateral and contralateral hemisphere after stroke. This increase starts already at 24 hours and lasts to at least 28 days post-stroke. More specifically, EphA4 expression is upregulated in old sprouting neurons following experimental stroke12,13. In mice with reduced levels of EphA4 or in whom EphA4 downstream signalling pathways have been pharmacologically blocked, functional recovery after experimental stroke is improved14. Furthermore, EphA4 knock out primary cortical neurons show increased neurite outgrowth compared to control cells, suggesting a role of EphA4 in formation of new neuronal projections, a mechanism that enhances stroke recovery14. Additionally, blocking ephrin-A5, a ligand for EphA4, has shown positive effects on neural plasticity and functional outcome after stroke15. Taken together, these findings suggest an important role of EphA4 in stroke recovery. Moreover, the availability of an EphA4 blocking peptide makes this receptor interesting for therapeutic manipulations. However, the underlying mechanisms as well as the best therapeutic window to target EphA4, in combination with rehabilitation training, remain unknown; therefore further research using different stroke models to validate our initial findings and to determine molecular mechanisms is of great interest.status: publishe