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Several olive oil phenolic compounds, such us oleuropein have attracted considerable attention because of their antioxidant activity, anti-atherosclerotic and anti-inflammatory properties. The aim of this experimental study was to determine the effect of oleuropein aglycone, a hydrolysis product of oleuropein, in the inflammatory response, in particular in the secondary injury associated with the mouse model of spinal cord trauma. The injury was induced by application of vascular clips to the dura via a four-level T5–T8 laminectomy in mice. Oleuropein aglycone was administered in mice (100 μg/kg, 40 μg/kg, 20 μg/kg, 10% ethanol, i.p.) 1 h and 6 h after the trauma. The treatment with oleuropein aglycone significantly decreased: (1) histological damage, (2) motor recovery, (3) nuclear factor (NF)-κB expression and IKB-α degradation, (4) protein kinase A (PKA) activity and expression, (5) pro-inflammatory cytokines production such as tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β), 6) inducible nitric oxide synthase (iNOS) expression, (7) neutrophil infiltration, (8) lipid peroxidation, (9) nitrotyrosine and poly-ADP-ribose (PAR) formation, (10) glial cell-derived neurotrophic factor (GDNF) levels, (11) apoptosis (TUNEL staining, FAS ligand expression, Caspase 3, Bax and Bcl-2 expression). Thus, we propose that olive oil phenolic constituents such as oleuropein aglycone may be useful in the treatment of various inflammatory diseases.