Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke

Functional recovery after stroke varies greatly between patients, potentially due to differences in gene expression. Several processes like angiogenesis, neurogenesis, axonal reorganization and synaptic plasticity act in concert to restore neurological functions. The ephrin family has known roles in all these processes. EphA4 is the most abundant ephrin receptor in the nervous system. Therefore, we investigated whether EphA4 affects functional recovery from stroke, and evaluated the potential of this receptor as a therapeutic target. Motor recovery after photothrombotic stroke was studied in transgenic mice in which expression of EphA4 was reduced. Furthermore, blocking a downstream target of EphA4, ROCK (Rho-associated kinase), by two different compounds was evaluated in the same model. Motor recovery after photothrombotic stroke was markedly enhanced in transgenic mice with reduced levels of EphA4, whereas infarct sizes were similar compared with non-transgenic controls. Pharmacological inhibition of the EphA4 signaling cascade using two ROCK inhibitors,Y-27632 and fasudil, improved motor function of mice after stroke. Infarct size was comparable in all groups studied, suggesting that the benefit obtained by EphA4 inhibition is not neuroprotective in nature but due to an effect on the mechanisms underlying recovery. Our findings show that reduction of EphA4 improves motor function after experimental stroke and demonstrate that ROCK inhibition is a promising therapeutic strategy to enhance recovery after ischemic stroke.