title: 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.
authors.affiliation: Department of Physiology, University of Puerto Rico Medical Science Campus, San Juan, Puerto Rico.
authors.forename: Johnny D
authors.initials: JD
authors.lastname: Figueroa
authors.forename: Richard L
authors.initials: RL
authors.lastname: Benton
authors.forename: Ixane
authors.initials: I
authors.lastname: Velazquez
authors.forename: Aranza I
authors.initials: AI
authors.lastname: Torrado
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ortiz
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Hernandez
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Diaz
authors.forename: David S
authors.initials: DS
authors.lastname: Magnuson
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Miranda
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D036141:Receptor, EphA7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; C093291:EPHA7 protein, rat; D036141:Receptor, EphA7; D010751:Phosphopyruvate Hydratase