Neuroprotection of hydroxysafflor yellow A in the transient focal ischemia: Inhibition of protein oxidation/nitration, 12/15-lipoxygenase and blood–brain barrier disruption

Hydroxysafflor yellow A (HSYA) is the main component of the safflower yellow pigments, the aqueous extract of safflower florets. We report here an experimental study for evaluating HSYA for their neuroprotective qualities on rats subjected to middle cerebral artery occlusion (60 min) and reperfusion (24 h), an experimental model in which excessive production of reactive oxygen and nitrogen species has been found. In our data, biochemical analysis of tissue proteins showed that cerebral ischemia/reperfusion (I/R) injury resulted in significant elevation of carbonyl groups and nitrotyrosine in the brain of I/R in comparison to sham controls, indicating the occurrence of oxidative/nitrative modification to brain proteins. HSYA-treatment (1, 5 and 10 mg/kg) inhibited I/R-induced protein oxidation and nitration. 12/15-Lipoxygenase (12/15-LOX), the enzyme implicated in oxidative stress of cerebral I/R, displayed overexpression in I/R rats. Elevated 12/15-LOX activity, estimated by the level of its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE), was also induced by the challenge of cerebral I/R. Administration of HSYA 1, 5 and 10 mg/kg reduced the upregulation of 12/15-LOX expression and activity in a dose-dependent manner. Moreover, the increase in blood–brain barrier (BBB) permeability evaluated by IgG leakage, Evans blue extravasation, and brain water content, respectively, was markedly alleviated by HSYA, indicating its protection against BBB disruption and brain edema following I/R insult. Taken together, these results demonstrate the neuroprotective properties of HSYA, which may be at least in part due to its potential to reduce protein oxidation and nitration, inhibit the upregulation of 12/15-LOX, and attenuate BBB breakdown.

► Hydroxysafflor yellow A (HSYA) inhibited protein oxidation and nitration induced by cerebral ischemia/reperfusion.
► HSYA reduced the upregulation of 12/15-lipoxygenase expression and activity.
► HSYA attenuated BBB disruption and brain edema following ischemia/reperfusion insult.
► The BBB protective roles of HSYA might be due to the inhibition of protein nitration and 12/15-lipoxygenase in microvessels.