TY - JOUR
T1 - Realgar and cinnabar are essential components contributing to neuroprotection of Angong Niuhuang Wan with no hepatorenal toxicity in transient ischemic brain injury
AU - Tsoi, Bun
AU - Wang, Songlin
AU - Gao, Chong
AU - Luo, Yunhao
AU - Li, Wenting
AU - Yang, Dan
AU - Yang, Depo
AU - Shen, Jiangang
N1 - Funding Information:
This study was supported by the Hong Kong Innovation and Technology Commission ITF grant ( UIM/289 ); the ITF Internship Programme ( InP/246/17 ); Hong Kong General Research Fund (GRF No. 17118717 ), Research Grant Council, Hong Kong SAR, China ; Grant from National Natural Science Foundation of China (No. 31570855 ) and Areas of Excellence Scheme ( AoE/P-705/16 ), Research Grant Council, Hong Kong SAR, China .
Funding Information:
We would like to express our gratitude to Ms. Xia Li and Ms. Wei WU from Beijing Tong Ren Tang Chinese Medicine Co. Ltd. for providing the AGNHW and modified formulas of AGNHW used in this study. We thank the Faculty Core Facility, Li Ka Shing Faculty of Medicine, The University of Hong Kong, for providing the Carl Zeiss LSM780 and LSM800 used in capturing confocal fluorescent images. Alternatively, we greatly appreciate Dr. Zhimin ZHAO and Mr. Bai BAI in School of Pharmaceutical Science; Ms. Minsi LIANG in Instrumental Analysis & Research Center of Sun Yat-sen University, Guangzhou, China, for their help in ICP-MS analysis. This study was supported by the Hong Kong Innovation and Technology Commission ITF grant (UIM/289); the ITF Internship Programme (InP/246/17); Hong Kong General Research Fund (GRF No. 17118717), Research Grant Council, Hong Kong SAR, China; Grant from National Natural Science Foundation of China (No. 31570855) and Areas of Excellence Scheme (AoE/P-705/16), Research Grant Council, Hong Kong SAR, China. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher Copyright:
© 2019
PY - 2019/8/15
Y1 - 2019/8/15
N2 - Realgar and cinnabar are commonly used mineral medicine containing arsenic and mercury in Traditional Chinese Medicine (TCM). Angong Niuhuang Wan (AGNHW) is a representative realgar- and cinnabar-containing TCM formula for treating acute ischemic stroke, but its toxicology and neuropharmacological effects are not well addressed. In this study, we compared the neuropharmacological effects of AGNHW and modified AGNHW in an experimental ischemic stroke rat model. Male SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 22 h of reperfusion. Although oral administration of AGNHW for 7 days in the rats increased arsenic level in the blood and liver tissue, there were no significant changes in the arsenic level in kidney, mercury level in the blood, liver and kidney as well as hepatic and renal functions in MCAO rats. AGNHW revealed neuroprotective properties by reducing infarction volume, preserving blood-brain barrier integrity and improving neurological functions against cerebral ischemia-reperfusion injury. Interestingly, removing realgar and/or cinnabar from AGNHW abolished the neuroprotective effects. Meanwhile, AGNHW could scavenge peroxynitrite, down-regulate the expression of p47phox, 3-NT and MMP-9 and up-regulate the expression of ZO-1 and claudin-5 in the ischemic brains, which were abolished by removing realgar and/or cinnabar from AGNHW. Notably, realgar or cinnabar had no neuroprotection when used alone. Taken together, oral administration of AGNHW for one week should be safe for treating ischemic stroke with neuroprotective effects. Realgar and cinnabar are necessary elements with synergetic actions with other herbal materials for the neuroprotective effects of AGNHW against cerebral ischemia-reperfusion injury.
AB - Realgar and cinnabar are commonly used mineral medicine containing arsenic and mercury in Traditional Chinese Medicine (TCM). Angong Niuhuang Wan (AGNHW) is a representative realgar- and cinnabar-containing TCM formula for treating acute ischemic stroke, but its toxicology and neuropharmacological effects are not well addressed. In this study, we compared the neuropharmacological effects of AGNHW and modified AGNHW in an experimental ischemic stroke rat model. Male SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 22 h of reperfusion. Although oral administration of AGNHW for 7 days in the rats increased arsenic level in the blood and liver tissue, there were no significant changes in the arsenic level in kidney, mercury level in the blood, liver and kidney as well as hepatic and renal functions in MCAO rats. AGNHW revealed neuroprotective properties by reducing infarction volume, preserving blood-brain barrier integrity and improving neurological functions against cerebral ischemia-reperfusion injury. Interestingly, removing realgar and/or cinnabar from AGNHW abolished the neuroprotective effects. Meanwhile, AGNHW could scavenge peroxynitrite, down-regulate the expression of p47phox, 3-NT and MMP-9 and up-regulate the expression of ZO-1 and claudin-5 in the ischemic brains, which were abolished by removing realgar and/or cinnabar from AGNHW. Notably, realgar or cinnabar had no neuroprotection when used alone. Taken together, oral administration of AGNHW for one week should be safe for treating ischemic stroke with neuroprotective effects. Realgar and cinnabar are necessary elements with synergetic actions with other herbal materials for the neuroprotective effects of AGNHW against cerebral ischemia-reperfusion injury.
KW - Angong Niuhuang Wan
KW - Cerebral ischemia-reperfusion injury
KW - Cinnabar
KW - Heavy metal toxicity
KW - Realgar
KW - Safety
UR - http://www.scopus.com/inward/record.url?scp=85067918778&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2019.114613
DO - 10.1016/j.taap.2019.114613
M3 - Journal article
C2 - 31207256
AN - SCOPUS:85067918778
SN - 0041-008X
VL - 377
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
M1 - 114613
ER -