Inhibition of EphA7 up‐regulation after spinal cord injury reduces apoptosis and promotes locomotor recovery

Abstract

Functional impairment after spinal cord injury (SCI) is partially attributed to neuronal cell death, with further degeneration caused by the accompanying apoptosis of myelin-forming oligodendrocytes. The Eph receptor protein tyrosine kinase family and its cognate ligands, the ephrins, have been identified to be involved in axonal outgrowth, synapse formation, and target recognition, mainly mediated by repulsive activity. Recent reports suggest that ephrin/Eph signaling might also play a role as a physiological trigger for apoptosis during embryonic development. Here, we investigated the expression profile of EphA7, after SCI, by using a combination of quantitative real-time PCR (QRT-PCR) and immunohistochemical techniques. QRT-PCR analysis showed an increase in the expression of full-length EphA7 at 7 days postinjury (DPI). Receptor immunoreactivity was shown mostly in astrocytes of the white matter at the injury epicenter. In control animals, EphA7 expression was observed predominantly in motor neurons of the ventral gray matter, although some immunoreactivity was seen in white matter. Furthermore, blocking the expression of EphA7 after SCI using antisense oligonucleotides resulted in significant acceleration of hindlimb locomotor recovery at 1 week. This was a transient effect; by 2 weeks postinjury, treated animals were not different from controls. Antisense treatment also produced a return of nerve conduction, with shorter latencies than in control treated animals after transcranial magnetic stimulation. We identified EphA7 receptors as putative regulators of apoptosis in the acute phase after SCI. These results suggest a functional role for EphA7 receptors in the early stages of SCI pathophysiology.

Molecular, Anatomical, Physiological, and Behavioral Studies of Rats Treated with Buprenorphine after Spinal Cord Injury

“…The tcMMEP was performed in treated animals; no responses were observed in injured animals treated or untreated with buprenorphine. The responses observed were similar to the traces reported by Cruz-Orengo et al (2007) and Figueroa et al (2006). This data suggests that the analgesic is not affecting the return of nerve conduction in sham or injured animals.…”

Guidance Molecules in Axon Regeneration

“…Additional evidence that ephrinEph signaling may play a role in CNS response to injury stems from reports showing upregulation of EphA3 in astrocytes after SCI in rats (Irizarry-Ramirez et al 2005). Similarly, EphA7 is up-regulated by SCI and is thought to be a regulator of apoptosis in rat astrocytes (Figueroa et al 2006). Thus, in addition to their role as growth inhibitory cues, Eph-ephrin signaling also influences formation of the glial scar and apoptosis.…”

Guidance Molecules in Axon Pruning and Cell Death

“…More recently, ephrin/Eph cues have been shown to be pro-apoptotic in other cellular contexts (Figueroa et al 2006;Noren et al 2006), but also in some cases they seem to act as prosurvival factors, at least in adult mouse neural stem cells (Furne et al 2009;Ricard et al 2006). In the latter case, it has been proposed that EphA4 may act as a dependence receptor that would promote cell death in the absence of ephrin ligands, following caspase cleavage processes similar to the ones described for DCC and Unc5 (Furne et al 2009).…”