title: Hydroxysafflor yellow A exerts neuroprotective effects in cerebral ischemia reperfusion-injured mice by suppressing the innate immune TLR4-inducing pathway.
abstract: The innate immune response, which is tightly regulated by Toll-like receptor 4 (TLR4) pathway, has been shown to play a critical role in brain damage following cerebral ischemia-reperfusion injury. Hydroxysafflor yellow A (HSYA) is the active component extracted from the Flos Carthami and has been reported to decrease neurological deficit scores following ischemia-reperfusion injury. However, the precise mechanism by which it exerts these neuroprotective effects remains poorly understood. In this study, we demonstrated that the administration of HSYA could significantly down-regulate TLR4 expression in middle cerebral artery occlusion (MCAO) mice. Following the down-regulation of TLR4 by HSYA treatment, cerebral infarction and inflammatory neuronal damage was alleviated. The number of apoptotic neurons in the HSYA-treated group was significantly decreased along with the decrease in TLR4 expression in MCAO mice. Activation of the NF-κB and MAPK signaling pathways was observed at 1h following ischemia and at 24h post-reperfusion. HSYA could significantly inhibit NF-κB p-p65, ERE1/2, JNK and p38 phosphorylation, which coincided with the suppressed secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nitric oxide (NO). Moreover, brain-derived neurotrophic factor (BDNF) was up-regulated following 1h of ischemia and continued to increase initially during reperfusion but was down-regulated at later stages. Following treatment with HSYA, BDNF was up-regulated relative to control MCAO mice at 1h post-ischemia and at 12 and 24h post-reperfusion. Our data suggest that HSYA exerts neurotrophic and anti-inflammatory functions against ischemic stroke by inhibiting TLR4 pathway-mediated signaling responses.
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Institute of Translational Medicine of Nanchang University, Nanchang 330001, China.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Qian
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Longsheng
authors.initials: L
authors.lastname: Fu
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Xuanying
authors.initials: X
authors.lastname: Chen
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Haili
authors.initials: H
authors.lastname: Zhong
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang 330006, China. Electronic address: 305260242@qq.com.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wei
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007113:Immunity, Innate / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011809:Quinones / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011809:Quinones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C085278:hydroxysafflor yellow A; D002599:Chalcone; D020928:Mitogen-Activated Protein Kinases
keywords: Anti-inflammatory; Cerebral ischemia reperfusion; Hydroxysafflor yellow A; Neuroprotective effects; Neurotrophy; TLR4