Following experimental stroke, the recovering brain is vulnerable to lipoxygenase-dependent semaphorin signaling.
FASEB J
; 27(2): 437-45, 2013 Feb.
Article
in En
| MEDLINE
| ID: mdl-23070608
ABSTRACT
Recovery from stroke is limited, in part, by an inhibitory environment in the postischemic brain, but factors preventing successful remodeling are not well known. Using cultured cortical neurons from mice, brain endothelial cells, and a mouse model of ischemic stroke, we show that signaling from the axon guidance molecule Sema3A via eicosanoid second messengers can contribute to this inhibitory environment. Either 90 nM recombinant Sema3A, or the 12/15-lipoxygenase (12/15-LOX) metabolites 12-HETE and 12-HPETE at 300 nM, block axon extension in neurons compared to solvent controls, and decrease tube formation in endothelial cells. The Sema3A effect is reversed by inhibiting 12/15-LOX, and neurons derived from 12/15-LOX-knockout mice are insensitive to Sema3A. Following middle cerebral artery occlusion to induce stroke in mice, immunohistochemistry shows both Sema3A and 12/15-LOX are increased in the cortex up to 2 wk. To determine whether a Sema3A-dependent damage pathway is activated following ischemia, we injected recombinant Sema3A into the striatum. Sema3A alone did not cause injury in normal brains. But when injected into postischemic brains, Sema3A increased cortical damage by 79%, and again, this effect was reversed by 12/15-LOX inhibition. Our findings suggest that blocking the semaphorin pathway should be investigated as a therapeutic strategy to improve stroke recovery.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arachidonate 12-Lipoxygenase
/
Arachidonate 15-Lipoxygenase
/
Brain
/
Stroke
/
Semaphorin-3A
Type of study:
Guideline
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2013
Document type:
Article
Affiliation country:
United States
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA