Abstract
Angong Niuhuang Wan (AGNHW) is a classic prescription in traditional Chinese medicine (TCM) used for stroke treatment, but its efficacies remain to be confirmed. With its arsenic- and mercury-containing materials, the application of AGNHW raises great safety concerns. Herein, we aim to explore the neuropharmacological effects against cerebral ischemia–reperfusion injury and evaluate the toxicological effects of AGNHW for better use. Male SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) and following 22 h of reperfusion. AGNHW (257 mg/kg, 1× AGNHW) were orally administered for pharmacological effects and 257, 514, and 1,028 mg/kg (equivalent to 1×, 2×, 4× AGNHW) were used for the toxicological study. The results revealed that AGNHW treatment reduced the infarct size and protected the blood–brain barrier (BBB) integrity in the MCAO rat ischemic stroke model. AGNHW treatment up-regulated bcl-2 expression and down-regulated the expressions of Bax, p47phox, inducible nitric oxide synthase (iNOS), and 3-nitrotyrosine (3-NT), and inhibited the expressions and activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and reserved tight junction protein zonula occludens-1 (ZO-1) and claudin-5 in the ischemic brains. These results indicated that the neuroprotective mechanisms of AGNHW could be associated with its antioxidant properties by inhibiting oxidative/nitrative stress-mediated MMP activation and protecting tight junction proteins in the ischemic brains. Administration of 1× AGNHW for 7 days would not induce the accumulation of mercury in blood, liver, and kidney at day 14. Administration of 2× AGNHW and 4× AGNHW for 7 days increased the level of mercury in the kidney. For arsenic level, administration of 1× AGNHW for 7 days would increase the level of arsenic in the liver and blood without increase of arsenic in the kidney at day 14. Administration of 2× AGNHW and 4× AGNHW for 7 days would further increase the level of arsenic in the liver and blood. There is no influence on body weight, organ index, histological structures, and renal and liver functions. These results suggest that short-term treatment of AGNHW within 1 week should be safe and has neuroprotective effects against cerebral ischemia–reperfusion injury.
Highlights
Stroke is the second cause of death (World Health Organization, 2018) and the leading cause of disability in human diseases (Feigin et al, 2017)
These data fell within the requirement of Angong Niuhuang Wan (AGNHW) as stated in the Chinese pharmacopeia, indicating that the AGNHW we used in this experiment was complied with the national standard
Results showed that the infarct portion in both striatum and lateral cortex of the left hemisphere was significantly reduced after oral administration of AGNHW (Figure 2B), and the extensive extravasation of Evans blue dye in the left hemisphere was decreased by AGNHW treatment (Figure 2C). These results suggested that AGNHW had neuroprotective effects against cerebral ischemia–reperfusion injury
Summary
Stroke is the second cause of death (World Health Organization, 2018) and the leading cause of disability in human diseases (Feigin et al, 2017). Serum MMPs are important biomarkers for predicting BBB disruption and HT in ischemic stroke patients. Clinical trials indicated that early plasma MMP-9 level was correlated with infarct severity and BBB damage, which could be used for predicting hemorrhagic complications in stroke patients (Castellanos et al, 2007). Recanalization with delayed thrombolysis could induce oxidative stress, mediate MMP activation, and lead to BBB disruption in cerebral ischemia– reperfusion injury (Gasche et al, 2001; Jian Liu and Rosenberg, 2005). Our recent studies indicated that PDC could prevent HT and improve neurological outcome in ischemic rat brains with delayed t-PA treatment via inhibiting peroxynitrite-mediated MMP activation (Chen et al, 2015). Targeting RNS-mediated MMP activation could be an important therapeutic strategy for protecting BBB integrity, improving therapeutic outcome and reducing cerebral ischemia– reperfusion injury during thrombolytic treatment
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