Hydroxysafflor Yellow A Shows Protection against PPARγ Inactivation in Nitrosative Neurons.

Abstract

Peroxynitrite-mediated nitrosative stress in the brain has been associated with various neurodegenerative disorders. Recent evidence highlights peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ 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 PPARγ nitration status and lack of activation of the receptor, as measured by PPARγ DNA-binding activity, by agonist (15d-PGJ2 or rosiglitazone) stimulation. The crucial role of PPARγ 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 PPARγ antagonist, aggravated SIN-1-induced neuronal injury. The addition of HSYA not only inhibited SIN-1-induced neuronal damage but prevented PPARγ nitrative modification and resumed PPARγ 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 PPARγ 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 PPARγ 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.

• Authors: Li Sun, Yan-Wei Xu, Jing Han, Chen Xiao, Shan-Shan Cao, Hao Liang, Yan Cheng
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2018 Pg. 9101740 ( 2018) ISSN: 1942-0994 [Electronic] United States
• PMID: 30410641 (Publication Type: Journal Article)

Chemical References

• Neuroprotective Agents
• PPAR gamma
• Quinones
• hydroxysafflor yellow A
• linsidomine
• Chalcone
• Molsidomine

Topics

• Animals
• Cell Death (drug effects)
• Cells, Cultured
• Chalcone (analogs & derivatives, chemistry, pharmacology)
• Hippocampus (pathology)
• Male
• Molsidomine (analogs & derivatives)
• Neurons (drug effects, metabolism)
• Neuroprotection (drug effects)
• Neuroprotective Agents (chemistry, pharmacology)
• Nitrosation
• PPAR gamma (agonists, metabolism)
• Quinones (chemistry, pharmacology)
• Rats, Sprague-Dawley