title: Capacity of HSYA to inhibit nitrotyrosine formation induced by focal ischemic brain injury.
abstract: Peroxynitrite-mediated protein tyrosine nitration represents a crucial pathogenic mechanism of stroke. Hydroxysafflor yellow A (HSYA) is the most important active component of the safflower plant. Here we assess the neuroprotective efficacy of HSYA and investigate the mechanism through anti-nitrative pathway. Rats were subjected to 60-min ischemia followed by reperfusion. HSYA (2.5-10mg/kg) was injected at 1h after ischemia onset. Other groups received HSYA (10mg/kg) treatment at 3-9h after onset. Infarct volume, brain edema, and neurological score were evaluated at 24h after ischemia. Nitrotyrosine and inducible NO synthase (iNOS) expression, as well as NO level (nitrate/nitrite) in ischemic cortex was examined within 24h after ischemia. The ability of HSYA to scavenge peroxynitrite was evaluated in vitro. Infarct volume was significantly decreased by HSYA (P<0.05), with a therapeutic window of 3h after ischemia at dose of 10mg/kg. HSYA treatment also reduced brain edema and improved neurological score (P<0.05). Nitrotyrosine formation was dose- and time-dependently inhibited by HSYA. The time window of HSYA in decreasing protein tyrosine nitration paralleled its action in infarct volume. HSYA also greatly reduced iNOS expression and NO content at 24h after ischemia, suggesting prevention of peroxynitrite generation from iNOS. In vitro, HSYA blocked authentic peroxynitrite-induced tyrosine nitration in bovine serum albumin and primary cortical neurons. Collectively, our results indicated that post-ischemic HSYA treatment attenuates brain ischemic injury which is at least partially due to reducing nitrotyrosine formation, possibly by the combined mechanism of its peroxynitrite scavenging ability and its reduction in iNOS production.
authors.affiliation: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, PR China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, PR China. Electronic address: sunli_2000@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Xu
authors.forename: Hao
authors.initials: H
authors.lastname: Liang
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000032:analysis / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000032:analysis / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
chemical_list: D011809:Quinones; C085278:hydroxysafflor yellow A; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D002599:Chalcone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: 3-NT; 3-nitrotyrosine; AG; BSA; Cerebral ischemia; HSYA; Hydroxysafflor yellow A; MCA; MCAO; NO; Nitric oxide synthase; Nitrotyrosine; ONOO(−); Peroxynitrite; aminoguanidine; bovine serum albumin; hydroxysafflor yellow A; iNOS; inducible NO synthase; middle cerebral artery; middle cerebral artery occlusion; nitric oxide; peroxynitrite