Neuroprotective Effect of Astragaloside IV on Cerebral Ischemia/Reperfusion Injury Rats Through Sirt1/Mapt Pathway.

Background: Ischemic stroke is a common disease with poor prognosis, which has become one of the leading causes of morbidity and mortality worldwide. Astragaloside IV (AS-IV) is the main bioactive ingredient of Astragali Radix (which has been used for ischemic stroke for thousands of years) and has been found to have multiple bioactivities in the nervous system. In the present study, we aimed to explore the neuroprotective effects of AS-IV in rats with cerebral ischemia/reperfusion (CIR) injury targeting the Sirt1/Mapt pathway. Methods: Sprague-Dawley rats (male, 250-280 g) were randomly divided into the Sham group, middle cerebral artery occlusion/reperfusion (MCAO/R) group, AS-IV group, MCAO/R + EX527 (SIRT1-specific inhibitor) group, and AS-IV + EX527 group. Each group was further assigned into several subgroups according to ischemic time (6 h, 1 d, 3 d, and 7 days). The CIR injury was induced in MCAO/R group, AS-IV group, MCAO/R + EX527 group, and AS-IV + EX527 group by MCAO surgery in accordance with the modified Zea Longa criteria. Modified Neurological Severity Scores (mNSS) were used to evaluate the neurological deficits; TTC (2,3,5-triphenyltetrazolium chloride) staining was used to detect cerebral infarction area; Western Blot was used to assess the protein levels of SIRT1, acetylated MAPT (ac-MAPT), phosphorylated MAPT (p-MAPT), and total MAPT (t-MAPT); Real-time Quantitative Polymerase Chain Reaction (qRT-PCR) was used in the detection of Sirt1 and Mapt transcriptions. Results: Compared with the MCAO/R group, AS-IV can significantly improve the neurological dysfunction (p < 0.05), reduce the infarction area (p < 0.05), raise the expression of SIRT1 (p < 0.05), and alleviate the abnormal hyperacetylation and hyperphosphorylation of MAPT (p < 0.05). While compared with the AS-IV group, AS-IV + EX527 group showed higher mNSS scores (p < 0.05), more severe cerebral infarction (p < 0.05), lower SIRT1 expression (p < 0.01), and higher ac-MAPT and p-MAPT levels (p < 0.05). Conclusion: AS-IV can improve the neurological deficit after CIR injury in rats and reduce the cerebral infarction area, which exerts neuroprotective effects probably through the Sirt1/Mapt pathway.

Sanhua Decoction, a Classic Herbal Prescription, Exerts Neuroprotection Through Regulating Phosphorylated Tau Level and Promoting Adult Endogenous Neurogenesis After Cerebral Ischemia/Reperfusion Injury.

Background: Ischemia stroke is the leading cause of death and long-term disability. Sanhua Decoction (SHD), a classic Chinese herbal prescription, has been used for ischemic stroke for about thousands of years. Here, we aim to investigate the neuroprotective effects of SHD on cerebral ischemia/reperfusion (CIR) injury rat models. Methods: The male Sprague-Dawley rats (body weight, 250-280 g; age, 7-8 weeks) were randomly divided into sham group, CIR group, and SHD group and were further divided into subgroups according to different time points at 6 h, 1, 3, 7, 14, 21, and 28 d, respectively. The SHD group received intragastric administration of SHD at 10 g kg-1 d-1. The focal CIR models were induced by middle cerebral artery occlusion according to Longa's method, while sham group had the same operation without suture insertion. Neurological deficit score (NDS) was evaluated using the Longa's scale. BrdU, doublecortin (DCX), and glial fibrillary acidic protein (GFAP) were used to label proliferation, migration, and differentiation of nerve cells before being observed by immunofluorescence. The expression of reelin, total tau (t-tau), and phosphorylated tau (p-tau) were evaluated by western blot and RT-qPCR. Results: SHD can significantly improve NDS at 1, 3, 7, and 14 d (p < 0.05), increase the number of BrdU positive and BrdU/DCX positive cells in subventricular zone at 3, 7, and 14 d (p < 0.05), upregulate BrdU/GFAP positive cells in the ischemic penumbra at 28 d after CIR (p < 0.05), and reduce p-tau level at 1, 3, 7, and 14 d (p < 0.05). There was no significant difference on reelin and t-tau level between three groups at each time points after CIR. Conclusions: SHD exerts neuroprotection probably by regulating p-tau level and promoting the proliferation, migration, and differentiation of endogenous neural stem cells, accompanying with neurobehavioral recovery.

Herbal Compatibility of Ginseng and Rhubarb Exerts Synergistic Neuroprotection in Cerebral Ischemia/Reperfusion Injury of Rats.

OBJECTIVE: Ischemic stroke is a complex multifactorial disease caused by interactions among polygenetic, environmental, and lifestyle factors with limited effective treatments. Multi-herbal formulae have long been used for stroke through herbal compatibility in traditional Chinese medicine (TCM); however, there is still a lack of evidence due to their unimaginable complexity. Herbal pairs represent the simplest and basic features of multi-herbal formulae, which are of great significance in clarifying herbal compatibility. Here, we aim to investigate the neuroprotective effects of the herbal compatibility of Ginseng and Rhubarb on a cerebral ischemia/reperfusion (I/R) injury model of rats. METHODS: Male adult SD rats were randomly divided into a sham group, a normal saline (NS) group, a Ginseng group, a Rhubarb group, and a Ginseng + Rhubarb (GR) group, a Carbenoxolone [CBX, gap junction (GJ) specific inhibitor] group, and a GR + CBX group. Each group was further assigned into four subgroups according to ischemic time (6 h, 1 day, 3 days, and 7 days). The cerebral I/R injury model was established according to the modified Zea Longa method. The Neurological Deficiency Score (NDS) was assessed by the Zea-Longa scale; the cerebral infarction area was detected by TTC (2,3,5-triphenyltetrazolium chloride) staining; and the expression of connexin-43 (Cx43) and aquaporin-4 (AQP4) were detected based on an immunofluorescence technique and quantitative real-time-PCR. RESULTS: Compared to the I/R group, both the independent and combined use of Ginseng and Rhubarb can significantly improve NDS (P < 0.05), decrease the percentage of the cerebral infarction area around the infarction penumbra (P < 0.05) and down-regulate the expression of Cx43 and AQP4 after I/R injury (P < 0.05). The GR had more significant effects than that of Ginseng and Rhubarb (P < 0.05). Compared with the GR group, the GR + CBX group significantly improved in NDS (P < 0.05), and decreased the percentage of the cerebral infarction area (P < 0.05) and expression of Cx43 and AQP4 protein (P < 0.05). CONCLUSION: The herbal compatibility of Ginseng and Rhubarb synergistically exerts neuroprotective function during acute cerebral I/R injury, mainly through reducing the expression of Cx43 and AQP4.

Efficacy and safety of Chinese herbal medicine for depression: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of Chinese herbal medicine (CHM) for depression. METHODS: An electronic search was conducted in eight databases from inception until April 2018. Randomized controlled trials with risk of bias (RoB) score ≥ 4 according to the Cochrane RoB tool were included for analyses. The primary outcome was the severity of depression. The secondary outcomes were total effective rate (TER) and adverse events. The minimally important difference (MID) of the severity of depression was a reduction in the Hamilton Rating Scale for Depression 17 items (HAMD-17) scores by 4. RevMan 5.3 Software was used for data analyses. GRADE system was used to assess the certainty of evidence. RESULTS: A total of 40 eligible studies with 3549 subjects were identified. Meta-analyses showed that CHM monotherapy had better clinically effects than placebo according to HAMD-17 score (Mean Difference (MD) = -4.53, 95% CI (-5.69, -3.37), P < 0.00001; Certainty of evidence: Moderate) and TER (Risk Ratio (RR) = 2.15, 95% CI (1.61, 2.88), P < 0.00001, Certainty of evidence: Low). Meta-analyses showed that CHM was as effective as western conventional medications (WCM) in TER (RR = 0.99, 95% CI (0.95, 1.02), P = 0.41, Certainty of evidence: High) and in reducing HAMD-17 score (MD = 0.44, 95% CI (-0.11, 0.99), P = 0.12, Certainty of evidence: Moderate). Meta-analyses showed that CHM in combination with WCM was better than WCM in TER (RR = 1.16, 95% CI (1.07, 1.27), P = 0.0004, Certainty of evidence: High), while had comparable clinically effects with WCM according to HAMD-17 score (MD = -2.51, 95% CI (-3.24, -1.77), P < 0.00001, Certainty of evidence: Moderate). In additional, CHM were associated with less adverse events than WCM, and adding CHM to WCM reduced adverse events. CONCLUSION: The findings of present systematic review, at least to a certain extent, provided supporting evidence for the routine use of CHM for depression.

Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism.

Borneol, a natural product in the Asteraceae family, is widely used as an upper ushering drug for various brain diseases in many Chinese herbal formulae. The blood-brain barrier (BBB) plays an essential role in maintaining a stable homeostatic environment, while BBB destruction and the increasing BBB permeability are common pathological processes in many serious central nervous system (CNS) diseases, which is especially an essential pathological basis of cerebral ischemic injury. Here, we aimed to conduct a systematic review to assess preclinical evidence of borneol for experimental ischemic stroke as well as investigate in the possible neuroprotective mechanisms, which mainly focused on regulating the permeability of BBB. Seven databases were searched from their inception to July 2018. The studies of borneol for ischemic stroke in animal models were included. RevMan 5.3 was applied for data analysis. Fifteen studies investigated the effects of borneol in experimental ischemic stroke involving 308 animals were ultimately identified. The present study showed that the administration of borneol exerted a significant decrease of BBB permeability during cerebral ischemic injury according to brain Evans blue content and brain water content compared with controls (P < 0.01). In addition, borneol could improve neurological function scores (NFS) and cerebral infarction area. Thus, borneol may be a promising neuroprotective agent for cerebral ischemic injury, largely through alleviating the BBB disruption, reducing oxidative reactions, inhibiting the occurrence of inflammation, inhibiting apoptosis, and improving the activity of lactate dehydrogenase (LDH) as well as P-glycoprotein (P-GP) and NO signaling pathway.

Chinese herbal medicine for headache: A systematic review and meta-analysis of high-quality randomized controlled trials.

BACKGROUND: Chinese herbal medicines (CHMs) are widely used to relieve headache in Asia. However, it is uncertain whether there is robust evidence on the effects of CHMs for headache. PURPOSE: To assess the effectiveness and safety of CHMs for headache using systematic review of high-quality randomized controlled trials (RCTs). METHODS: Electronic search was conducted on six databases from inception to January 2018. We included the RCTs that met the requirement of at least 4 out of the 7 domains according to the Cochrane risk of bias tool. RESULTS: Thirty RCTs with 3447 subjects were ultimately included for analysis and all trials were conducted in Asia. Meta-analysis showed that CHMs monotherapy were superior to placebo in reducing headache frequency [SMD -0.48 (95% CI -0.76, -0.20); p < 0.01], headache days [SMD -0.29 (95% CI -0.45, -0.13); p < 0.01], headache duration[SMD -0.58 (95% CI -0.81, -0.36); p < 0.01], headache intensity [SMD -0.42 (95% CI -0.62, -0.23); p < 0.01] and analgesic consumption [SMD -0.36 (95% CI -0.52, -0.21); p < 0.01] and improving clinical efficacy rate (p < 0.01). Similarly, CHMs monotherapy were superior to western conventional medicines (WCMs) in headache frequency [SMD -0.57 (95% CI -0.84, -0.29); p < 0.01], headache days (p < 0.01), analgesic consumption [SMD -1.63 (95% CI -1.98, -1.28); p < 0.01], headache intensity [SMD -0.81 (95% CI -1.06, -0.57); p < 0.01], and clinical efficacy rate [RR 1.24 (95% CI 1.18, 1.31); p < 0.01], except reducing headache duration (p > 0.05). CHMs adjunct therapy can improve clinical efficacy rate compared with WCMs alone [RR 1.15 (95% CI 1.09, 1.22); p < 0.01]. Meanwhile, CHMs had fewer adverse events than that of controls. CONCLUSION: The findings supported, at least to an extent, the use of CHM for headache patients; however, we should treat the results cautiously because the clinical heterogeneity.

Erxian decoction, a Chinese herbal formula, for menopausal syndrome: An updated systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Erxian decoction (EXD), a famous Chinese herbal prescription, consists of Rhizoma Curculiginis, Herba Epimedii, Radix Morindae Officinalis, Radix Angelicae Sinensis, Cortex Phellodendri, Rhizoma Anemarrhenae, all of which are recorded in the Chinese Pharmacopoeia. OBJECTIVE: To conduct an updated systematic and meta-analysis investigating efficacy and safety of EXD for menopausal syndrome. METHODS: An electronic search was conducted in eight databases from inception until July 2018. Randomized controlled trials with risk-of-bias score ≥ 7 according to the Cochrane Back Review Group were included for analyses. All participants with a diagnosis of menopausal syndrome met the established criteria. The treatment group was EXD monotherapy or adjunct therapy. Comparators were placebo, hormone replace therapy, hormone plus nonhormonal agents, nonhormonal agents and no treatment. The primary outcome measurements were the Kupperman index, total hot flush scores, total menopause rating scale (MRS) scores and total menopause-specific quality of life (MENQOL) scores. The secondary outcomes were total clinical effective rate, traditional Chinese medicine (TCM) syndrome scores, Hamilton depression (HAMD) scale scores, self-rating depression scale (SDS) scores, self-Rating Anxiety Scale (SAS) scores, athens insomnia scale (AIS) scores, serological indicators, blood pressure, and adverse events. RevMan 5.3 Software was used for data analyses. GRADE system was used to assess the level of evidence. RESULTS: Sixteen eligible studies with 1594 subjects were identified. Five studies showed EXD was contradictory results according to Kupperman index of menopausal syndrome compared with hormone. One study showed EXD significantly improved total hot flush scores, total MRS scores and total MENQOL scores compared with placebo (P < 0.05). Meta-analysis of 10 EXD monotherapy or 2 paratherapy studies showed that both can significantly improve total effective rate compared with hormone (P < 0.05); 3 studies showed that EXD plus hormone significantly reduces the TCM syndrome scores, HAMD scale scores, SDS scores and SAS scores compared with hormone (P < 0.05). One study showed a significant effect of EXD for reducing AIS scores compared with hormone (P < 0.05); 7 studies showed contradictory effects for improving serological indicators compared with hormone. Two studies reported adverse effects, whereas the other studies did not mention. The quality of the evidence of primary outcomes was moderate to high according to the GRADE profiler. CONCLUSIONS: The present findings do not allow an assessment of the evidence because the low-quality studies included cannot be reproduced. However, we identified an area, which is worthy of further research. Rigorous RCTs are still needed in the future.

Buyang Huanwu Decoction Targets SIRT1/VEGF Pathway to Promote Angiogenesis After Cerebral Ischemia/Reperfusion Injury.

Background: Ischemia stroke is known as the major cause of morbidity and mortality. Buyang Huanwu Decoction (BHD), a classical traditional Chinese medicine (TCM) formula, has been used to prevent and treat stoke for hundreds of years. The purpose of present study is to investigate the effects of BHD on angiogenesis in rats after cerebral ischemia/reperfusion (I/R) injury targeting Silent information regulator 1 (SIRT1) / Vascular endothelial growth factor (VEGF) pathway. Methods: The cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO). Adult Sprag-Dawley (SD) rats were randomly divided into five groups: sham group, normal saline (NS) group, BHD group, BHD+EX527 (SIRT1 specific inhibitor) group, and NS+EX527 group. Each group was divided into the subgroups according to 1, 3, 7, or 14 days time-point after cerebral ischemia/reperfusion, respectively. Neurological function score (NFS) was evaluated by the Rogers scale; microvascular density (MVD) in brain tissue around infarction area was observed by immunofluorescence; and the expression of SIRT1 and VEGF was assessed by Western Blot and Quantitative Real-time-PCR. Results: BHD can significantly improve NFS (P < 0.05), increase the MVD in the boundary ischemic area (P < 0.01) and elevate the expression of protein and mRNA of SIRT1 and VEGF following I/R injury (P < 0.01). In contrast, treatment with EX527 reversed the BHD-induced improvements in NFS (P < 0.01) and decreased the MVD (P < 0.01) and the expression of SIRT1 and VEGF (P < 0.05). Conclusion: BHD exerts neuroprotection targeting angiogenesis through the up-regulation of SIRT1/VEGF pathway against cerebral ischemic injury in rats.

Herbal Medicine Formulas for Parkinson's Disease: A Systematic Review and Meta-Analysis of Randomized Double-Blind Placebo-Controlled Clinical Trials.

Background: Parkinson's disease (PD) is a debitlitating, chronic, progressive neurodegenerative disorder without modifying therapy. Here, we aimed to evaluate the available evidence of herbal medicine (HM) formulas for patients with PD according to randomized double-blind placebo-controlled clinical trials. Methods: HM formulas for PD were searched in eight main databases from their inception to February 2018. The methodological quality was assessed using Cochrane Collaboration risk of bias tool. Meta-analysis was performed using RevMan 5.3 software. Results: Fourteen trials with Seventeen comparisons comprising 1,311 patients were identified. Compared with placebo groups, HM paratherapy (n = 16 comparisons) showed significant better effects in the assessments of total Unified Parkinson's Disease Rating Scale (UPDRS) (WMD: -5.43, 95% CI:-8.01 to -2.86; P < 0.0001), UPDRS I (WMD: -0.30, 95% CI: -0.54 to -0.06; P = 0.02), UPDRS II (WMD: -2.21, 95% CI: -3.19 to -1.22; P < 0.0001), UPDRS III (WMD: -3.26, 95% CI:-4.36 to -2.16; P < 0.00001), Parkinson's Disease Quality of Life Questionnaire (p < 0.01) and Parkinson's Disease Questionnaire-39 (WMD: -7.65, 95% CI: -11.46 to -3.83; p < 0.0001), Non-motor Symptoms Questionnaire (p < 0.01) and Non-Motor Symptoms Scale (WMD: -9.19, 95% CI: -13.11 to -5.28; P < 0.00001), Parkinson's Disease Sleep Scale (WMD: 10.69, 95% CI: 8.86 to 12.53; P < 0.00001), and Hamilton depression rating scale (WMD: -5.87, 95% CI: -7.06 to -4.68; P < 0.00001). The efficiency of HM monotherapy (n = 1 comparison) was not superior to the placebo according to UPDRS II, UPDRS III and total UPDRS score in PD patients who never received levodopa treatment, all P > 0.05. HM formulas paratherapy were generally safe and well tolerated for PD patients (RR: 0.41, 95% CI: 0.21 to 0.80; P = 0.009). Conclusion: The findings of present study supported the complementary use of HM paratherapy for PD patients, whereas the question on the efficacy of HM monotherapy in alleviating PD symptoms is still open.

Chuanxiong Formulae for Migraine: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials.

Objective: Migraine is a complex, prevalent and disabling neurological disorder characterized by recurrent episodes of headache without ideal treatment. We aim to assess the current available evidence of herbal Chuanxiong (Ligusticum chuanxiong Hort. root) formulae for the treatment of migraine according to the high-quality randomized controlled trials (RCTs). Methods: English and Chinese electronic databases were searched from their inceptions until March 2017. The methodological quality of included study was assessed by the Cochrane Collaboration risk of bias tool. RCTs with Cochrane risk of bias (RoB) score ≥4 were included in the analyses. Meta-analysis was conducted using RevMan 5.3 software. Publication bias was assessed by funnel plot analysis and Egger's test. Results: Nineteen RCTs with 1832 participants were identified. The studies investigated the Chuanxiong formulae vs. placebo (n = 5), Chuanxiong formulae vs. conventional pharmacotherapy (CP) (n = 13 with 15 comparisons), and Chuanxiong formulae plus CP vs. CP (n = 1). Meta-analysis indicated that Chuanxiong formulae could reduce frequency, duration, days and pain severity of migraine and improve the total clinical efficacy rate (P < 0.05). Adverse event monitoring was reported in 16 out of 19 studies and occurrence rate of adverse event was low. Conclusion: The findings of present study indicated that Chuanxiong formulae exerted the symptom reliefs of for migraine.

Chinese Herbal Medicine for Vascular Dementia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials.

BACKGROUND: Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD. OBJECTIVE: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD. METHODS: Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan 5.3 was applied for data analysis. RESULTS: Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n = 4), CHM versus western conventional treatment (WCT) (n = 36), and CHM plus WCT versus WCT (n = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa's dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group. CONCLUSION: The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD.