Hydroxysafflor Yellow A Shows Protection against PPARγ Inactivation in Nitrosative Neurons

Peroxynitrite‐mediated nitrosative stress in the brain has been associated with various neurodegenerative disorders. Recent evidence highlights peroxisome proliferator‐activated receptor γ (PPAR γ ) as a critical neuroprotective factor in neurodegenerative diseases. Here, we observed the effect of the herb hydroxysafflor yellow A (HSYA) during nitrosative stress in neurons and investigated the mechanism based on PPAR γ protection. We found that a single exposure of primary neurons to peroxynitrite donor SIN‐1 caused neuronal injury, which was accompanied by the increase of PPAR γ nitration status and lack of activation of the receptor, as measured by PPAR γ DNA‐binding activity, by agonist (15d‐PGJ2 or rosiglitazone) stimulation. The crucial role of PPAR γ in neuronal defense against nitrosative stress was verified by showing that pretreatment with 15d‐PGJ2 or rosiglitazone attenuated SIN‐1‐induced neuronal injury but pretreatment with GW9662, a PPAR γ antagonist, aggravated SIN‐1‐induced neuronal injury. The addition of HSYA not only inhibited SIN‐1‐induced neuronal damage but prevented PPAR γ nitrative modification and resumed PPAR γ activity stimulated by either 15d‐PGJ2 or rosiglitazone. Furthermore, HSYA also showed the ability to rescue the neuroprotective effect of 15d‐PGJ2 or rosiglitazone when the agonists were coincubated with SIN‐1. Finally, in vivo experiments demonstrated that the administration of HSYA also efficiently blocked PPAR γ nitration and loss of activity in the SIN‐1‐injected hippocampus and reversed the increased neuronal susceptibility which was supported by the inhibition of Bcl‐2 protein downregulation induced by SIN‐1. The results suggest that HSYA protects neurons from nitrosative stress through keeping PPAR γ as a functional receptor, allowing a more effective activation of this neuroprotective factor by the endogenous or exogenous agonist. Our findings provide new clues in understanding the role of the neuroprotective potential of the herbal HSYA.