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: Yanni Lv, Yisong Qian, Longsheng Fu, Xuanying Chen, Haili Zhong, Xiaohua Wei
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 769 Pg. 324-32 (Dec 15 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 26607471 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• NF-kappa B
• Neuroprotective Agents
• Quinones
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• hydroxysafflor yellow A
• Chalcone
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Chalcone (analogs & derivatives, pharmacology, therapeutic use)
• Immunity, Innate (drug effects)
• Infarction, Middle Cerebral Artery (complications)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Quinones (pharmacology, therapeutic use)
• Reperfusion Injury (complications, drug therapy, metabolism, pathology)
• Signal Transduction (drug effects, immunology)
• Toll-Like Receptor 4 (metabolism)
• Up-Regulation (drug effects)