Neurotherapeutic Effects of Pueraria mirifica Extract in Early- and Late-Stage Cognitive Impaired Rats.
Anukulthanakorn Kanya,Parhar Ishwar S,Jaroenporn Sukanya,Kitahashi Takashi,Watanbe Gen,Malaivijitnond Suchinda
Phytotherapy research : PTR
We determined the neurotherapeutic effects of Pueraria mirifica extract (PME) and pure puerarin (PU) in comparison with 17β-estradiol (E2 ) in early- and late-stage cognitive impaired rats. Rats were ovariectomized (OVX), kept for 2 and 4 months to induce early- and late-stage cognitive impairment, respectively, and divided into four groups that were treated daily with (i) distilled water, (ii) 100 mg/kg of PME, (iii) 7 mg/kg of PU, and (iv) 80 µg/kg of E2 for 4 months. The estrogen deficiency symptoms of OVX rats were abrogated by treatment with E2 or PME, but not by treatment with PU. The mRNA level of genes associated with amyloid production (App and Bace1) and hyperphosphorylated Tau (Tau4) were upregulated together with the level of impaired cognition in the 2- and 4-month OVX rats. Treatment with E2 reduced the level of cognitive impairment more than that with PME and PU, and 2-month OVX rats were more responsive than 4-month OVX rats. All treatments down-regulated the Bace1 mRNA level in 2-month OVX rats, while PU and PME also decreased the App mRNA level in 2- and 4-month OVX rats, respectively. Only PU suppressed Tau4 expression in 2-month OVX rats. Thus, PME and PU elicit neurotherapeutic effects in different pathways, and earlier treatment is optimal. Copyright © 2016 John Wiley & Sons, Ltd.
Active compounds of herbs ameliorate impaired cognition in APP/PS1 mouse model of Alzheimer's disease.
Yu WenJun,An ShengJun,Shao TieMei,Xu HongJun,Chen HongXu,Ning JunDa,Zhou YongJie,Chai XiQing
Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by amyloid plaque accumulations, intracellular tangles and neuronal loss in certain brain regions. It has been shown that a disturbance of normal iron metabolism contributes to the pathophysiology of AD. However, the mechanism underlying abnormal iron load in the brain of AD patients is unclear. The frontal cortex, an important brain structure for executive function, is one of the regions affected by AD. We investigated the beneficial effects of active compounds of Epimedium, Astragaoside and Puerarin on iron metabolism in the frontal cortex of six-month-old APPswe/PS1 (APP/PS1) double transgenic mouse, a model of AD. Treatment with the active compounds reduced cognitive and memory deficits and damaged cell ultrastructure in APP/PS1 mice. These beneficial effects were associated with changes in expression levels of iron metabolism proteins in the frontal cortex, including divalent metal transporter with iron response element (DMT1-with IRE), divalent metal transporter without iron response element (DMT1-without IRE), transferrin (TF) and transferring receptor 1 (TfR1); three release proteins including the exporter ferroportin 1 (Fpn1), ceruloplasmin (CP) and hephaestin (HEPH), one increased storage iron protein ferritin and one iron regulating hormone hepcidin. These findings suggest that the active compounds improve cognition and memory in brain neurodegenerative disorders and these beneficial effects are associated with reduced impairment of iron metabolism. This study may provide a new strategy for developing novel drugs to treat AD.
Brain Pharmacokinetics and the Pharmacological Effects on Striatal Neurotransmitter Levels of Isoflavonoids in Rat.
Xiao Bingxin,Sun Zengxian,Cao Fangrui,Wang Lisha,Liao Yonghong,Liu Xinmin,Pan Ruile,Chang Qi
Frontiers in pharmacology
Isoflavonoids are putatively active components of and has been demonstrated prominent neuro-protection effect against cerebrovascular disorders, hypertension or Parkinson's disease (PD). However, the molecular basis for the beneficial effect of on nervous systems has not been well revealed. The present study aims to assess striatum exposure to main active isoflavonoids and changes of striatal extracellular neurotransmitters levels in rat brain after intravenous administration of isoflavonoids extracts (PLF), to further elucidate its' substantial bases for neuro activities. Fifteen rats were divided into 3 groups (five rats in each group) to receive a dose of PLF at 80 or 160 mg/kg or normal saline (vehicle), respectively. An LC-MS/MS method was employed to determine the concentrations of five main isoflavonoids and multiple neurotransmitters in microdialysate from striatal extracellular fluid (ECF) of the rats. The exposed quantities of puerarin (PU), 3'-methoxypuerarin (MPU), daidzein-8-C-apiosyl-(1-6)-glucoside (DAC), and 3'-hydroxypuerarin (HPU) in striatum were dose-dependent. The content of daidzein (DAZ) was too low to be detected in all dialysate samples through the experiment. Optimal dose PLF (80 mg/kg) promoted DA metabolism and inhibited 5-HT metabolism. No obvious change in the level of GLu was determined. The concentration of GABA presented a temporary decline firstly and then a gradual uptrend followed by a further downtrend. Higher dose (160 mg/kg) PLF could enhance the metabolism of both DA and 5-HT, and lower the extracellular level of GLu, without changing GABA concentrations, which might result in alleviation on excitatory toxicity under conditions, such as ischemia. The results infer that different dose of PLF should be chosen to achieve appropriate neurochemical modulation effects under conditions, such as hypertension or ischemia/stroke. These findings may significantly contribute to a better understanding of the neuroprotective effect of and provide new insights into its application toward neuro-degenerative diseases in the future.
Therapeutic Effects of Puerarin Against Anterior Ischemic Optic Neuropathy Through Antiapoptotic and Anti-Inflammatory Actions.
Nguyen Ngo Le Minh-Anh,Wen Yao-Tseng,Ho Yu-Chieh,Kapupara Kishan,Tsai Rong-Kung
Investigative ophthalmology & visual science
Purpose:This study investigated the therapeutic effects of puerarin (PR) on a rat model of anterior ischemic optic neuropathy (rAION). Methods:The neuroprotective effects of PR on rAION were evaluated using flash visual-evoked potentials (FVEP), retrograde labeling of retinal ganglion cells (RGCs), TUNEL assay of the retina, optical coherence tomography (OCT) images of optic nerve width, and ED1 staining of the optic nerve (ON). The inflammatory response of ON and Akt signaling pathways were analyzed through Western blot. M2 polarization was determined by immunostaining and immunoblotting in ONs. Results:In FVEP analysis, the amplitude of P1-N2 and the RGC density in the PR-treated group were 2.3- and 1.6-fold higher than those in the PBS-treated group, respectively (P < 0.05). The number of apoptotic RGC in the PR-treated group was 2.8-fold lower than that in the PBS-treated group. OCT images demonstrated that PR treatment-reduced ON edema in the acute phase compared to PBS treatment (P < 0.05). Macrophage infiltration was reduced by 5.2-fold by PR treatment compared with the PBS treatment (P < 0.05). PR treatment inhibited the levels of iNOS, IL-1β, and TNF-α, induced the levels of IL-10, Arg1, and Fizz1 in the rAION model. The levels of p-Akt1 and C/EBPβ in the PR-treated group increased by 3.4-fold and 5.89-fold compared with those in the PBS-treated group (P < 0.05). Inhibition of Akt activation reduced the number of M2 macrophage in the PR-treated group (P < 0.05). Conclusions:PR treatment provided the neuroprotective effects in the rAION model, which may lead to new clinical applications.
Effect of puerarin on transcriptome of astrocyte during oxygen-glucose deprivation/reoxygenation injury.
Wei Shuyong,Tong Jie,Xue Qiang,Liu Yang,Xu Xiaoyu
Molecular and cellular biochemistry
Stroke is a serious disease with complex pathomechanism and limited therapeutic effect in clinic. Our previous research has found obvious therapeutic effect of Puerarin (Pur) on stroke injury of rat. The aim of this study is to investigate the transcriptome changes of oxygen-glucose deprivation/reoxygenation (OGD/R)-injured astrocytes before and after the intervention of Pur. Cells activity and apoptosis detection indicated that the activity of OGD/R-injured astrocytes was improved, and the apoptosis was ameliorated by Pur. Affymetrix GeneChip Rat Genome 230 2.0 Array assays indicated that after intervention of Pur, mRNA expressions of 31 genes were up-regulated and 40 genes were down-regulated in OGD group, whereas mRNA expression of 36 genes were up-regulated, and 88 genes were down-regulated in OGD/R group. Pathway analysis indicated that the olfactory transduction pathway and the JAK (janus kinase) 2/STAT (signal transducer and activator of transcription) three pathways were down-regulated by Pur during OGD/R injury of astrocytes. These data indicated that Pur regulates transcriptome and expresses protective effect on astrocytes during OGD/R injury, and may be a potential therapeutic agent for the treatment of stroke.
The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats.
Zhang Dapeng,Ma Guozhang,Hou Mingming,Zhang Tao,Chen Limin,Zhao Chengbin
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND:Acute spinal cord injury (SCI) leads to permanent disabilities. This study evaluated the neuroprotective effect of puerarin, a natural extract, in a rat model of SCI. METHODS:Acute SCI models were established in rats using a modified Allen's method. Locomotor function was evaluated using the BBB test. The histological changes in the spinal cord were observed by H&E staining. Neuron survival and glial cells activation were evaluated by immunostaining. ELISA and realtime PCR were used to measure secretion and gene expression of cytokines. TUNEL staining was used to examine cell apoptosis and western blot analysis was used to detect protein expression. RESULTS:Puerarin significantly increased BBB score in SCI rats, attenuated histological injury of spinal cord, decreased neuron loss, inhibited glial cells activation, alleviated inflammation, and inhibited cell apoptosis in the injured spinal cords. In addition, the downregulated PI3K and phospho-Akt protein expression were restored by puerarin. CONCLUSION:Puerarin accelerated locomotor function recovery and tissue repair of SCI rats, which is associated with its neuroprotection, glial cell activation suppression, anti-inflammatory and anti-apoptosis effects. These effects may be associated with the activation of PI3K/Akt signaling pathway.
Puerarin and betahistine treatment of vertebrobasilar ischemia vertigo: A meta-analysis of randomized controlled trials.
Chen Yan-Yan,Chen Wen,Zhang Qing,Li Hui,Zhang Ye-Wen,Kang Qian,Lan Y I,Wu Qing
Experimental and therapeutic medicine
The present meta-analysis aimed to evaluate the effectiveness and safety of puerarin co-treatment with betahistine in treating vertebrobasilar ischemia (VBI) vertigo. A total of 6 medical databases were searched, identifying randomized controlled trials (RCTs) of VBI vertigo performed until August 2014 that investigated a combined treatment of puerarin with betahistine or with other conventional drugs. The quality of the literature was evaluated using the Cochrane Collaboration's tool for assessing risk of bias, and Rev Man 5.0 software was used for statistical analysis and evaluation. The present study included 7 RCTs, involving a total of 664 subjects, and revealed a statistically significant increase in efficacy between the control and the experimental group (odds ratio [OR], 4.99; 95% confidence interval [CI], 3.05 to 8.15). The average blood flow velocity within the vertebrobasilar arteries increased following treatment with puerarin and betahistine compared with that of the control groups (OR, 7.59; 95% CI, 6.19 to 9.00); however, no difference was detected between these groups in the average flow velocity within the left vertebral artery (OR, 6.17; 95% CI, 5.22 to 7.13). The frequency of adverse reactions in the experimental group was lower (OR, 0.75; 95% CI, 0.32 to 1.77) compared with the control group. Combined puerarin and betahistine regimens were more effective in treating VBI vertigo compared with other, conventional drugs; effectively alleviating the associated symptoms, including dizziness and increased average blood flow velocity within the vertebrobasilar arteries, without causing an increased number of serious side effects. However, the efficacy and safety of puerarin and betahistine use in treating VBI vertigo requires additional investigation.
Puerarin Protects Human Neuroblastoma SH-SY5Y Cells against Glutamate-Induced Oxidative Stress and Mitochondrial Dysfunction.
Zhu Xue,Wang Ke,Zhang Kai,Lin Xiufeng,Zhu Ling,Zhou Fanfan
Journal of biochemical and molecular toxicology
Glutamate, the principal excitatory neurotransmitter, plays a central role in brain metabolism; however, aberrant neurotransmission of glutamate has been linked to neurodegenerative diseases. Therefore, the effective agents that target at glutamate-induced cell injury will be useful for prevention and treatment of neurodegenerative diseases. In this study, the neuroprotective effect of puerarin, an active isoflavone extracted from the Chinese herb Radix puerariae, against glutamate-induced cell injury in human neuroblastoma SH-SY5Y cells was evaluated for the first time. The results showed that the pretreatment of puerarin could attenuate glutamate-induced cell injury in a dose-dependent manner. This protective effect was mediated through inhibiting reactive oxygen species generation, attenuating the upregulation of Bax and downregulation of Bcl-2, preserving mitochondrial membrane potential (MMP), preventing cytochrome c release, and reducing caspase activity. These findings may significantly contribute to a better understanding of the neuroprotective effect of puerarin and provide new insights into its application toward neurodegenerative diseases in the future.
Effects of puerarin combined with conventional therapy on ischemic stroke.
Yuan Min,Liu Guijiang,Zheng Xiuqi,Li Pei,Liu Jinghua,Wang Sujie,Cao Yibin
Experimental and therapeutic medicine
This study evaluated the use of conventional therapy combined with puerarin on ischemic stroke. Eighty patients with ischemic stroke admitted to Tangshan Gongren Hospital from March 2014 to September 2015 were randomly divided into two groups. The control group was treated with conventional therapy. The observation group was treated with an additional puerarin injection of 400 mg/day. The patients in both groups were examined for clinical neurological signs and symptoms. The levels of biochemical markers as well as changes in hemorheology were measured after the intervention and compared among the groups. Our results indicate that the language expression was significantly better in the observation group after the intervention (p<0.05). Additionally, the aphasia quotient was higher (p<0.05), the neurological deficit score was lower (p<0.05), and the functional ability score was higher (p<0.05). The plasma S-100B and NSE levels were lower (p<0.05), the whole blood viscosity and plasma viscosity were lower (p<0.05), and the levels of corticotropin-releasing hormone, corticotropin, cortisol, adrenaline and norepinephrine were lower (p<0.05). Our findings led to the conclusion that the use of puerarin can effectively improve the language function, reduce neurological damage, reduce blood viscosity, reduce stress response and improve quality of life.
Puerarin Ameliorates D-Galactose Induced Enhanced Hippocampal Neurogenesis and Tau Hyperphosphorylation in Rat Brain.
Hong Xiao-Ping,Chen Tao,Yin Ni-Na,Han Yong-Ming,Yuan Fang,Duan Yan-Jun,Shen Feng,Zhang Yan-Hong,Chen Ze-Bin
Journal of Alzheimer's disease : JAD
Enhanced neurogenesis has been reported in the hippocampus of patients with Alzheimer's disease (AD), the most common neurodegenerative disorder characterized with amyloid-β (Aβ) aggregation, tau hyperphosphorylation, and progressive neuronal loss. Previously we reported that tau phosphorylation played an essential role in adult hippocampal neurogenesis, and activation of glycogen synthase kinase (GSK-3), a crucial tau kinase, could induce increased hippocampal neurogenesis. In the present study, we found that treatment of D-galactose rats with Puerarin could significantly improve behavioral performance and ameliorate the enhanced neurogenesis and microtubule-associated protein tau hyperphosphorylation in the hippocampus of D-galactose rat brains. FGF-2/GSK-3 signaling pathway might be involved in the effects of Puerarin on hippocampal neurogenesis and tau hyperphosphorylation. Our finding provides primary in vivo evidence that Puerarin can attenuate AD-like enhanced hippocampal neurogenesis and tau hyperphosphorylation. Our finding also suggests Puerarin can be served as a treatment for age-related neurodegenerative disorders, such as AD.
Protective effects of puerarin on acute lung and cerebrum injury induced by hypobaric hypoxia via the regulation of aquaporin (AQP) via NF-κB signaling pathway.
Wang Chi,Yan Muyang,Jiang Hui,Wang Qi,Guan Xu,Chen Jingwen,Wang Chengbin
OBJECTIVE:Hypobaric hypoxia, frequently encountered at high altitude, may lead to lung and cerebrum injury. Our study aimed to investigate whether puerarin could exert ameliorative effects on rats exposed to hypobaric hypoxia via regulation of aquaporin (AQP) and NF-κB signaling pathway in lung and cerebrum. MATERIALS AND METHODS:40 Sprague Dawley rats were divided into four groups (normal control group, hypobaric hypoxia group, puerarin group and dexamethasone group). Wet/dry ratio, blood gas, pathological changes of lung and cerebrum and spatial memory were observed in each group. Inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were determined with ELISA and expression of AQP1, AQP4, NF-κB signaling pathway in lung and cerebrum with western blot RESULTS: Puerarin showed significant preventative effects on tissue injury and behavioral changes, as evidenced by histopathological findings and Morris water maze. In addition, levels of inflammatory cytokines in BALF decreased in the two preventative groups compared with those of hypobaric hypoxia group. AQP in lung and cerebrum increased under the condition of hypobaric hypoxia while was down regulated in both two preventative groups. NF-κB and IκB was also inhibited by puerarin. CONCLUSION:Our study suggested that lung and cerebrum injury, increased inflammatory cytokines in BALF and increased AQP1, AQP4 and NF-κB signaling pathway occurred under the condition of hypobaric hypoxia. Moreover, puerarin could prevent lung and cerebrum injury of rats exposed to hypobaric hypoxia via down-regulation of inflammatory cytokines, AQP1 and AQP4 expression and NF-κB signaling pathway.
Puerarin reduces apoptosis in rat hippocampal neurons culturea in high glucose medium by modulating the p38 mitogen activated protein kinase and c-Jun N-terminal kinase signaling pathways.
Xu Xiaohan,Wang Jingbo,Zhang Hong,Tian Guoqing,Liu Yuqin
Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan
OBJECTIVE:To investigate the neuroprotective etfect of puerarin on rat hippocampal neurons cultured in high glucose medium, and to examine the role of the p38 mitogen activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways in this effect. METHODS:Primary cultures of hippocampal neurons were prepared from newborn Sprague Dawley rats. Neuron-specific enolase immunocytochemistry was used to identify neurons. The neurons were cultured with normal medium (control group) or with high-glucose medium (high-glucose group), and puerarin (puerarin group), a p38 MAPK inhibitor (SB239063; p38 MAPK inhibitor group) or a JNK inhibitor (SP600125; JNK inhibitor group) were added. After 72 h of treatment, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was performed to detect apoptosis, and western blotting was used to assess protein levels of p-p38, p38, p-JNK and JNK. RESULTS:In the high-glucose group, the neuronal apoptosis rate and the p-p38/p38 and p-JNK/JNK ratios were higher than in the control group. The p38 MAPK and JNK inhibitors prevented this increase in the apoptosis rate. The apoptosis rates in the puerarin group, the p38 MAPK inhibitor group and the JNK inhibitor group were significantly decreased compared with the high-glucose group. Moreover, protein levels of p-p38 and p-JNK were significantly reduced, and the p-p38/p38 and p-JNK/JNK ratios were decreased in the puerarin group compared with the high-glucose group. In addition, compared with the high-glucose group, p-p38 levels and the p-p38/p38 ratio were reduced in the p38 MAPK inhibitor group, and p-JNK levels and the p-JNK/JNK ratio were decreased in the JNK inhibitor group. CONCLUSION:Puerarin attenuates neuronal apoptosis induced by high glucose by reducing the phosphorylation of p38 and JNK.
Synergistic Effects of Salvianolic Acid B and Puerarin on Cerebral Ischemia Reperfusion Injury.
Ling Chengli,Liang Jianming,Zhang Chun,Li Ruixiang,Mou Qianqian,Qin Jin,Li Xiaofang,Wang Jianxin
Molecules (Basel, Switzerland)
Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite significant progresses achieved, effective treatment still remains a formidable challenge due to the complexity of the disease. Salvianolic acid B (Sal-B) and Puerarin (Pue) are two active neuroprotectants isolated from traditional Chinese herbs, Salvia miltiorrhiza and Kudzu root respectively, which have been used for the prevention and treatment of IS for thousands of years in China. The activities of two compounds against cerebral ischemia reperfusion injury have been confirmed via various pathways. However, the therapeutic efficacy of any of the two components is still unsatisfied. In the present study, the effect of the combination of Sal-B and Pue on IS was evaluated and validated in vitro and in vivo. The ratio of two compounds was firstly optimized based on the results of CoCl₂ damaged PC12 cells model. The co-administration exhibited significantly protective effect in CoCl₂ induced PC12 cells injury model by reducing ROS, inhibiting apoptosis and improving mitochondrial membrane potential in vitro. Moreover, Sal-B + Pue significantly relieved neurological deficit scores and infarct area than Sal-B or Pue alone in vivo. The results indicated that neuroprotection mechanism of Sal-B + Pue was related to TLR4/MyD88 and SIRT1 activation signaling pathway to achieve synergistic effect, due to the inhibition of NF-κB transcriptional activity and expression of pro-inflammatory cytokine (TNF-α, IL-1β, IL-6). In conclusion, the combination of Sal-B and Pue exerted much stronger neuroprotective effect than Sal-B or Pue alone, which provides a potential new drug and has great significance for the treatment of IS.
Protective Effect of Puerarin Against Oxidative Stress Injury of Neural Cells and Related Mechanisms.
Cheng Yuan,Leng Wei,Zhang Jingshu
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Parkinson's disease (PD) is manifested as degeneration of dopaminergic neurons in substantia nigra compacta. The mitochondrial dysfunction induced by oxidative stress is believed to a major cause of PD. Puerarin has been widely applied due to its estrogen nature and anti-oxidative function. This study thus investigated the protective role of puerarin against oxidative stress injury on PC12 neural cells, in addition to related mechanisms. MATERIAL AND METHODS PC12 cells were pre-treated with gradient concentrations of puerarin, followed by the induction of 0.5 mM H2O2. MTT assay was used to detect cell viability. Enzyme-linked immunosorbent assay (ELISA) was employed to detect intracellular level of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH). Cell apoptosis was determined by Annexin-V/7-AAD double labelling. Reactive oxidative species (ROS) and lactate dehydrogenase (LDH) activities were then measured. Cellular levels of caspase-3 and caspase-9 were also determined. RESULTS The pre-treatment using puerarin significantly reversed H2O2-induced oxidative stress injury, as it can increase proliferation, SOD and GSH activities, decrease MDA activity, suppress apoptosis of PC12 cells, and decrease ROS and LDH production (p<0.05 in all cases). Further assays showed depressed up-regulation of caspase-3 and caspase-9 after puerarin pretreatment. CONCLUSIONS Puerarin pretreatment can decrease activity of caspase-3 and caspase-9 activity in PC12 cells, thus protecting cells from oxidative injury.
Puerarin promoted proliferation and differentiation of dopamine-producing cells in Parkinson's animal models.
Shiying Liu,Xinhui Qu,Guanghua Jin,Feng Nie,Feng Liu,Shumei Chen,Fan Hu
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BACKGROUND:Parkinson's disease (PD) is caused by the gradual loss of dopamine-producing cells in the brain. This study evaluated the potential neuroprotective role of puerarin (PR) on dopamine (DA)-producing cells in vitro and in vivo. METHOD:In vitro, the effects of PR on proliferation and differentiation and DA releases of mesenchymal stem cells (MSCs) were assayed by CCK-8, flow cytometry, real-time PCR and ELISA respectively. Then the differentiated cells were labeled with enhanced green fluorescent protein (EGFP) and administrated into PD animal models induced by 6-OHDA. The proliferation and differentiation of labeled cells were identified by fluorescence microscopy and immunostaining. RESULTS:In vitro, after being treated with different concentrations of PR for 1 week, the TUJ1, TH and DAT protein and mRNA expression and DA releases increased significantly. In vivo, after transplantation of PR-treated DA-producing cells, the symptoms of PD improved significantly from the second week after transplantation; more transplanted cells survived and migrated to wider region along injection line; more transplanted cells proliferated and differentiated into TH cells; more DA was detected in the striatum during 6 weeks' observation. CONCLUSION:The results suggest that PR promote DA neuron survival, proliferation and differentiation.
[Puerarin alleviates cognitive impairment and tau hyperphosphorylation in APP/PS1 transgenic mice].
Mei Zheng-Rong,Tan Xiang-Ping,Liu Shao-Zhi,Huang Han-Hui
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
To observe the effect of puerarin on learning and memory function and tau phosphorylation in APP/PS1 transgenic mice, drugs were administered to 3-month old APP/PS1 transgenic mice. Learning and memory function of mice were assessed by Morris water maze test 3 months after treatment. Animals were decapitated after behavioral test. The levels of Aβ were detected by ELISA, the expression of protein [tau, phosphorylated tau, GSK3β and p-GSK3β(Ser9)] were assessed by Western blot. Morris water maze test showed that the escape latency of APP/PS1 double transgenic mice was significantly longer than that of the normal control group, and the residence time of the original quadrant was significantly shorter. The escape latency of puerarin group was significantly shorter and the residence time of the original quadrant was prolonged compared with the model group. Compared with the normal control group, the levels of Aβ in the cortex of APP/PS1 transgenic mice were increased, the expression of phosphorylated tau was significantly increased, and the expression of phosphorylated GSK3β(Ser9) protein was decreased. Treatment with puerarin, the latency of APP/PS1 transgenic mice was significantly reduced, the level of Aβ was decreased, the expression of phosphorylated tau was significantly decreased, and the expression of phosphorylated GSK3β(Ser9) protein was increased. Puerarin improves the learning and memory impairment by reducing the formation of Aβ, activating the GSK3β signaling pathway, inhibiting the phosphorylation of tau in APP/PS1 double transgenic mice.
Puerarin for ischaemic stroke.
Liu Bian,Tan Yan,Wang Deren,Liu Ming
The Cochrane database of systematic reviews
BACKGROUND:Puerarin, a form of herbal medicine, is widely used in the treatment of ischaemic stroke in China. OBJECTIVES:To assess the effects of puerarin in people with ischaemic stroke. SEARCH METHODS:We searched the Cochrane Stroke Group Trials Register and the Chinese Stroke Trials Register (last searched August 2015). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 7), MEDLINE (1948 to August 2015), EMBASE (1980 to August 2015), AMED (the Allied and Complementary Medicine Database, 1985 to August 2015) and the China Biological Medicine Database (CBM-disc 1979 to August 2015). We searched reference lists, relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies. SELECTION CRITERIA:Randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials comparing puerarin with placebo or open control (no placebo) in people with ischaemic stroke. DATA COLLECTION AND ANALYSIS:Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted the data. MAIN RESULTS:We included 20 RCTs with 1574 participants in this updated review. All trials were published in Chinese language journals. We included 14 trials that we had excluded in the previous version of the review after we added a new outcome in this update. Time windows within which the participants were randomised ranged from 4.5 hours to 10 days. Ischaemic stroke was confirmed by computerised tomography (CT) or magnetic resonance imaging (MRI) in 18 trials. Meta-analysis of two trials with 164 participants showed that treatment with puerarin did not reduce death or dependency at final follow-up (RR 0.79, 95% CI 0.45 to 1.36). One trial with 83 participants reported that the mean value of the Barthel Index in the puerarin group was below that in the control group. Meta-analysis of 16 trials with 1305 participants showed that puerarin reduced the proportion of participants without improvement of neurological deficit at the end of follow-up (RR 0.42, 95% CI 0.33 to 0.55). None of the included trials reported serious adverse effects.The quality of evidence was low due to incomplete reporting of the methods and short-term follow-up. AUTHORS' CONCLUSIONS:There is not enough evidence to evaluate the effect of puerarin on survival or dependency in people with ischaemic stroke. High quality and large-scale RCTs with long-term follow-up are needed to assess its efficacy.
Protective Effects of Puerarin against Aβ 1-42-Induced Learning and Memory Impairments in Mice.
Wu Lidan,Tong Tong,Wan Shutong,Yan Tingxu,Ren Fangyi,Bi Kaishun,Jia Ying
Puerarin is a major isoflavone glycoside from the root of It has been reported that puerarin can protect neurons from oxidative stress-induced apoptosis. Emerging evidence suggests that oxidative damage is associated with A-induced neuronal death. In the current study, we evaluated the effect of puerarin on Alzheimer's disease induced by A and explored the potential mechanisms underlying this effect. We found that the escape latency of the Morris water maze was decreased in groups treated with puerarin compared to the model group (p < 0.01). In addition, there were significant differences between treated groups and the model group mice in a Y-maze test (p < 0.01). Furthermore, puerarin recovered the levels of brain-derived neurotrophic factor, phosphorylated tau, malondialdehyde, acetylcholine esterase, glycogen synthase kinase-3beta, and the activity of superoxide dismutase to some extent in the hippocampus and cerebral cortex. Shrinkage of nuclei and swollen and eccentrically dispersed neuronal bodies were observed in the hippocampus of A-treated mice. These data demonstrate that puerarin might protect against cognitive deficits, oxidative stress, and neurodegeneration induced by A.
Anticerebral Ischemia-Reperfusion Injury Activity of Synthesized Puerarin Derivatives.
Ji Yubin,Jiang Pei,Yan Xinjia
BioMed research international
When cerebral ischemia-reperfusion injury happened in patients, multiple pathological processes occur, such as leukocyte infiltration, platelet, and complement activation, which would result in cognitive dysfunction and inflammation. Puerarin has shown protective effect on injury of neural cell. In order to enhance this protective effect of puerarin, puerarin derivatives with different log values were designed and synthesized. The original phenolic hydroxyl in the puerarin molecules was substituted in order to change the blood-brain barrier permeability and thus enhance the efficacy for preventing cerebral ischemia/reperfusion injury. And the structure of the newly synthesized molecules was confirmed by 1H NMR spectroscopy and mass spectrometry. The mouse model of cerebral artery ischemia/reperfusion injury was established to test the anticerebral ischemia-reperfusion injury activity of the puerarin derivatives. The assays of the water maze, Y maze, brain cortex Ca-Mg-ATP enzyme, and iNOS enzyme activity were performed in this mouse model. The results showed that puerarin derivative P1-EA and P2-EA were resulting in an increased lipophilicity that enabled the derivatives to pass more efficiently through the blood-brain barrier, thus, improving the protective effects against cerebral ischemia/reperfusion injury. Therefore, derivatives of puerarin may serve as promising approach to improve neuron function in ischemia-reperfusion brain injury-related disorders.
Neuroprotective Effect of Puerarin on Glutamate-Induced Cytotoxicity in Differentiated Y-79 Cells via Inhibition of ROS Generation and Ca(2+) Influx.
Wang Ke,Zhu Xue,Zhang Kai,Wu Zhifeng,Sun Song,Zhou Fanfan,Zhu Ling
International journal of molecular sciences
Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca(2+) influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu root, has been widely used in the clinical treatment of retinal degenerative diseases in China for decades; however, the detailed molecular mechanism underlying this effect remains unclear. In this study, the neuroprotective effect of puerarin against glutamate-induced cytotoxicity in the differentiated Y-79 cells was first investigated through cytotoxicity assay. Then the molecular mechanism of this effect regarding anti-oxidative stress and Ca(2+) hemostasis was further explored with indirect immunofluorescence, flow cytometric analysis and western blot analysis. Our study showed that glutamate induced cell viability loss, excessive reactive oxygen species (ROS) generation, calcium overload and up-regulated cell apoptosis in differentiated Y-79 cells, which effect was significantly attenuated with the pre-treatment of puerarin in a dose-dependent manner. Furthermore, our data indicated that the neuroprotective effect of puerarin was potentially mediated through the inhibition of glutamate-induced activation of mitochondrial-dependent signaling pathway and calmodulin-dependent protein kinase II (CaMKII)-dependent apoptosis signal-regulating kinase 1(ASK-1)/c-Jun N-terminal kinase (JNK)/p38 signaling pathway. The present study supports the notion that puerarin may be a promising neuroprotective agent in the prevention of retinal degenerative diseases.
Radical Scavenging Activity of Puerarin: A Theoretical Study.
Zhou Huakang,Li Xiangzhou,Shang Yaxuan,Chen Kai
Antioxidants (Basel, Switzerland)
Puerarin is a C-glycoside of daidzein, one of the major bioactive ingredients isolated from the root of , which has a wide spectrum of pharmacological effects. Although puerarin is well-known for its effective antioxidant activity, there is seldom a systematic theoretical study on its radical scavenging activity. Herein, the free radical scavenging ability of puerarin was investigated systematically by density functional theory (DFT) calculations. The reaction activity was compared with daidzein as well. Three reaction pathways: hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) were discussed and compared by thermodynamic parameters such as bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE). The reaction kinetics of puerarin with special radicals •OH and •OOH were also studied. The results obtained may be of great significance for better understanding the relationship between the antioxidant properties and structural design of puerarin, as well as other antioxidants.
Puerarin prevents inflammation and apoptosis in the neurocytes of a murine Parkinson's disease model.
Jiang M,Yun Q,Niu G,Gao Y,Shi F,Yu S
Genetics and molecular research : GMR
The aim of this study was to investigate Parkinson's disease (PD) using a murine model of PD. Specifically, we aimed to explore the mechanism by which puerarin prevents inflammation and apoptosis in neurocytes. Eighty healthy male C57/BL6 mice were randomly selected and divided into four groups (N = 20 each): control group; PD group; PD+puerarin group; and puerarin group. At the end of the treatment period, the animals' brains were removed after perfusion and decollation. The protein expression levels of tyrosine hydroxylase (TH) in the murine brains were assessed by immunohistochemistry and the protein expression levels of TH, glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), cleaved Caspase-3, and Bax in the substantia nigra and corpus striatum of the animals were assessed by western blotting. The spontaneous activity of the PD mice was found to be significantly higher after puerarin treatment and the distance traveled by mice in an open field assessment was 1700 cm further in puerarin-treated PD mice than in PD mice. Immunohistochemistry and western blotting analyses indicated that the expression of TH was significantly higher (2.63-fold) in puerarin-treated PD mice than in untreated PD mice and that the expression of GFAP in PD mice was significantly reduced (~45%) by puerarin treatment. These findings lead us to conclude that puerarin significantly alleviates 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine-induced injury in dopaminergic neurons. Puerarin mediates anti-apoptotic and anti-inflammatory activities and plays a neuroprotective role.
Puerarin ameliorates cognitive deficits in streptozotocin-induced diabetic rats.
Liu Xianchu,Mo Yanzhi,Gong Jingbo,Li Zhuang,Peng Huan,Chen Jiaxue,Wang Qichao,Ke Zhaowen,Xie Jingtao
Metabolic brain disease
Previous research has indicated that Diabetes is a high risk of learning and memory deficits. Puerarin, an isoflavonoid extracted from Kudzu roots, has been reported to possess antioxidant, anti-inflammatory, anti-apoptotic and anti-diabetic properties which are useful in the treatment of various diseases. Recently, Puerarin was found to have the effects on learning and memory performances in humans and animal models. However, up to now, there is no detailed evidence on the effect of Puerarin on diabetes-associated cognitive decline (DACD). In this study, we designed to assess the effects of Puerarin on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model and exploring its potential mechanism. Diabetic rats were treated with Puerarin (100 mg/kg per d) for 7 days. The learning and memory function was evaluated by morris water maze test. The acetylcholinesterase (AChE), choline acetylase (ChAT), oxidative indicators [malondialdehyde (MDA) and superoxide dismutase (SOD)] and inflammatory cytokine (TNF-a, IL-1β and IL-6) were measured in hippocampus by using corresponding commercial kits. mRNA and Protein levels of Bcl-2 were analyzed by RT-PCR and Westernblot. The results showed that supplementation of Puerarin improved the learning and memory performances compared with the STZ group by the morris water maze test. In addition, Puerarin supplement significantly prevented AChE and MDA activities, increased ChAT and SOD activities, and alleviated the protein level of TNF-α, IL-1β and IL-6 in the hippocampus compared with the STZ group. Moreover, the pretreatment with Puerarin also significantly increased the Bcl-2 expression. It is concluded that Puerarin possesses neuroprotection to ameliorate cognitive deficits in streptozotocin-induced diabetic rats by anti-inflammatory, antioxidant and antiapototic effects.
[Pharmaceutics research advances in oral administration of puerarin].
Wu Wen-Ting,Zou Bin,Li Wen-Dong,Zhu Wei-Feng
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Puerarin is a naturally occurring isoflavone C-glycoside,isolated from the root of Pueraria lobata,which has attracted extensive attention in the medical circles because of its various pharmacological effects,such as vasodilation,cardioprotection,neuroprotection,antioxidant,anticancer,anti-inflammation,alleviating pain,promoting bone formation,inhibiting alcohol intake,and attenuating insulin resistance. However,its low oral bioavailability has limited its clinical application. This review gives a comprehensive summary of the researches on physicochemical properties,pharmacokinetics( absorption,distribution,metabolism and excretion,pharmacokinetic parameters) in oral administration,and pharmaceutics research strategies of puerarin in recent years,and the in vivo behavior difference between multicomponent and single component environment was also summarized. The reasons( low water solubility,poor membrane permeability,short half-life,inhibition of P-gp efflux and first-pass metabolic effects of intestinal enzymes,etc.) for low bioavailability were concluded and the idea that multicomponent enviroment would affect the bioavailability was clarified. The aim of this review is to provide literature basis for the development of new dosage forms and new technologies for multivariate compound drug delivery system to improve the bioavailability of oral puerarin,and to propose ways to improve the bioavailability of BCS Ⅳ drugs derived from traditional Chinese medicine by fully enlarging the synergistic effect of multi-components or reasonably using the inhibitory effect between components.
GPR30 Activation Contributes to the Puerarin-Mediated Neuroprotection in MPP-Induced SH-SY5Y Cell Death.
Cheng Yue-Fa,Zhu Guoqi,Wu Qing-Wen,Xie Yue-Sheng,Jiang Yan,Guo Lan,Guan Ya-Li,Liu Ying-Shuo,Zhang Jun
Journal of molecular neuroscience : MN
The neuroprotective action of puerarin in Parkinson's disease (PD) models has been well investigated. However, the mechanisms involved in protection have not been completely understood. G protein-coupled receptor 30 (GPR30) is a G protein-coupled estrogen receptor and considered a potential target in the neuroprotection against PD. In this study, we investigated whether puerarin prevented against 1-methyl-4-phenylpyridinium (MPP)-induced cell death via GPR30. Our results showed that the GPR30 agonist, G1, exhibited puerarin-mediated neuroprotection against MPP-induced cell death of SH-SY5Y cells. This protective action was reversed by the GPR30 antagonist. Moreover, a time- and concentration-dependent effect of puerarin on GPR30 expression was verified at the protein level but not at the mRNA level. Further, we showed that an mTor-dependent new GPR30 synthesis contributed to the protection conferred by puerarin. Finally, glial cell line-derived neurotrophic factor (GDNF) levels were enhanced by puerarin and G1 in both control and MPP-lesioned cells via GPR30. Taken together, our data strongly suggest that puerarin prevents MPP-induced cell death via facilitating GPR30 expression and GDNF release.
Puerarin suppression of Aβ-induced primary cortical neuron death is largely dependent on ERβ.
Li Li,Xue Zuguang,Chen Lei,Chen Xueyu,Wang Heshuang,Wang Xiaobo
Recent study has suggested that estrogen replacement therapy (ERT) can decrease the risk of the development of Alzheimer's disease (AD), and phytoestrogen has been proposed as a potential alternative to ERT. In this study, we investigated the protective function of puerarin (a phytoestrogen isolated from puerarin lobate) against amyloid beta (Aβ)-induced toxicity in cortical neurons and established the connection between such a protection and estrogen receptor (ER) activation. Puerarin suppressed Aβ-induced cortical neuron death in a concentration-dependent manner. Morphological examination showed that puerarin not only suppressed Aβ-induced decrease in neuron numbers, but also promoted neurite growth. In addition, we found that the neuroprotection of puerarin was dependent on the activation of estrogen receptors (ERs), as demonstrated by activation of ERE-reporter gene. Puerarin preferentially up-regulated the expression of ERβ but not ERα, and ERβ-specific siRNA significantly reduced the neuroprotection of puerarin. Taken together, our results indicated that puerarin is neuroprotective against Aβ toxicity via the activation of estrogen receptors, and ERβ plays a key role in the process. Our novel findings provide a potential strategy for the prevention of neurodegeneration and the treatment of AD.
The in silico and in vivo evaluation of puerarin against Alzheimer's disease.
Liu Song,Cao Xiao-Lu,Liu Guang-Qi,Zhou Tong,Yang Xi-Liang,Ma Bing-Xin
Food & function
The root of Pueraria lobata has been utilized as a food source for thousands of years in China. Puerarin is the major bioactive and the most abundant secondary metabolite obtained from the root of P. lobata. The potential therapeutic effect of puerarin against Alzheimer's disease was screened by in silico methods and confirmed by the amyloid β-peptide-induced Alzheimer's disease (AD) rat model. The in silico study displayed that puerarin had the potential to penetrate across the blood-brain barrier and had high stability in molecular docking and dynamics simulation with acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2) and caspase-3 (C3), which play a central role in the development of AD. The in vivo results showed that puerarin could restrain the AChE activity, restore the activities of antioxidant defense substances toward normal levels, and decrease the expression of inflammatory factors and apoptosis genes in the brain, especially down-regulating the expressions of COX-2 and C3. The histopathological examination of brain sections and behavioral testing also verified the biochemical observations, which further validates the in silico study. These results not only suggest that puerarin, as a potential compound, could relieve AD, but also broaden the applications of puerarin.
Puerarin inhibits β‑amyloid peptide 1‑42‑induced tau hyperphosphorylation via the Wnt/β‑catenin signaling pathway.
Yao Ying,Chen Xianchun,Bao Yuting,Wu Yangsheng
Molecular medicine reports
Excessive tau protein phosphorylation is important in the pathogenesis and early abnormal signal transduction of Alzheimer's disease. Excessive phosphorylation of microtubules is associated with tau accumulation, which induces the formation of neurofibrillary tangles in neurons, leading to synaptic damage and ultimately, neurodegeneration. The present study aimed to investigate the possible mechanism underlying the inhibitory effects of puerarin on β‑amyloid peptide (Aβ)1‑42‑induced tau protein hyperphosphorylation in SH‑SY5Y cells. Following various treatments, the viability of SH‑SY5Y cells was determined using the MTT assay, and cell morphology was observed under an inverted fluorescence microscope. Western blotting was used to detect tau phosphorylation, and the protein expression levels of glycogen synthase kinase (GSK)‑3β, phosphorylated (p)‑GSK‑3β (Ser9), β‑catenin and cyclin D1, which are the key factors mediating the Wnt/β‑catenin signaling pathway in SH‑SY5Y cells. The results demonstrated that puerarin reversed the Aβ1‑42‑induced decrease in SH‑SY5Y cell viability. In addition, puerarin inhibited the degree of Aβ1‑42‑induced tau phosphorylation at Ser396, Ser199 and Thr231 in SH‑SY5Y cells, and reduced the expression of GSK‑3β by increasing the expression of p‑GSK‑3β (Ser9). Furthermore, puerarin increased the protein expression levels of β‑catenin and cyclin D1, which are key factors involved in the Wnt/β‑catenin signaling pathway. The results of the present study demonstrated that puerarin may attenuate Aβ1‑42‑induced tau hyperphosphorylation in SH‑SY5Y cells, by inhibiting the expression of GSK‑3β and activating the Wnt/β‑catenin signaling pathway; therefore, puerarin may exert protective effects against Alzheimer's disease.
Puerarin attenuates locomotor and cognitive deficits as well as hippocampal neuronal injury through the PI3K/Akt1/GSK-3β signaling pathway in an model of cerebral ischemia.
Tao Jinhao,Cui Yuehua,Duan Yu,Zhang Nan,Wang Congmin,Zhang Fayong
Ischemic stroke causes irreversible damage to the brain. The hippocampus is a vulnerable region and plays an important role in cognition and locomotor activity. Puerarin is a phytoestrogen that has beneficial effects in treating neurological disorders. How puerarin protects against hippocampal injury and its molecular mechanisms remain to be elucidated. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with puerarin alone or together with LY294002 (an PI3K inhibitor) before ischemia/reperfusion (I/R). The open- and closed-field tasks and Morris water maze (MWM) test were used to assess the effects of puerarin on anxiety-like behavioral and cognitive impairment following I/R. Hematoxylin-eosin staining(HE) was used to examine the survival of hippocampal CA1 pyramidal neurons, and immunoblotting was performed to examine the expression of the related proteins. By using the rat model for transient I/R, we demonstrated that puerarin pretreatment significantly increased the travelling distance and number of crossings in the open- and closed-field tests, reduced latency and increased the proportion of distance and time in zone IV in the MWM. The number of live cells in the hippocampus is sharply increased by puerarin pretreatment.We further observed that the levels of phosphorylated Akt1, GSK-3β and MCL-1were elevated and those of cleaved-caspase-3 were reduced in the puerarin-treatment group. Notably, the PI3K inhibitor LY294002 counteracted all of the effects of puerarin. Our findings suggest that puerarin protects the hippocampus from I/R damage by activating the PI3K/Akt1/GSK-3β/MCL-1 signaling pathway.
Efficacy and safety of puerarin injection in curing acute ischemic stroke: A meta-analysis of randomized controlled trials.
Zheng Qing-Hua,Li Xiao-Li,Mei Zhi-Gang,Xiong Li,Mei Qing-Xian,Wang Jin-Feng,Tan Ling-Jing,Yang Song-Bai,Feng Zhi-Tao
BACKGROUND:Previous studies indicated that the puerarin injection has been widely employed in China for the treatment of acute ischemic stroke. We aim to evaluate the efficacy and safety of the puerarin injection for the treatment of acute ischemic stroke. METHODS:A systematic literature search was performed in PUBMED, EMBASE, SPRINGER LINK, Scopus, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Journals Database, Wanfang database and the China Biological Medicine database before November 2016, randomized controlled clinical trials (RCTs) of puerarin injection treating acute ischemic stroke were included. In addition, we searched reference lists of relevant retrieved articles. Two authors extracted data independently. The effective rate, the neurologic deficit score, the blood rheology indexes, and fibrinogen were assessed and analyzed by the Review Manager 5.3 software. The continuous variables were expressed as MD with 95% CI and dichotomous data used RR or ORs. Adverse reactions related to the puerarin injection were also examined. RESULTS:Thirty-five RCTs with a total of 3224 participants were identified in the meta-analysis. The combined results of 32 trials indicated that the puerarin injection was better than control drugs at the clinical effective rate (RR 1.22, 95% CI 1.17 to 1.28, P < 0.001) and 16 studies showed the neurological deficit was significantly improved (MD -3.69, 95% CI -4.67 to -2.71, P < 0.001); the hemorheology index and fibrinogen were much lower with the puerarin injection when compared with western conventional medicines (WCM) or other control drugs (the whole blood viscosity: MD -0.89, 95% CI -1.37 to -0.41, P < 0.001; the HCT: MD -0.04, 95% CI -0.06 to -0.02, P < 0.001; the fibrinogen: MD -0.64, 95% CI -0.96 to -0.31, P < 0.001). Eleven trials reported that the adverse reactions related to the puerarin injection included facial flushing, dizziness, vomiting, nausea, and other mild gastrointestinal discomfort and allergic reaction. No serious adverse drug reactions were reported. CONCLUSIONS:Puerarin injection may be more effective and relatively safe in clinic for treating acute ischemic stroke. However, the current evidence is insufficient due to the poor methodological quality and lack of adequate safety data. Further RCTs are required to examine its efficacy.
Puerarin protects rat brain against ischemia/reperfusion injury by suppressing autophagy the AMPK-mTOR-ULK1 signaling pathway.
Wang Jin-Feng,Mei Zhi-Gang,Fu Yang,Yang Song-Bai,Zhang Shi-Zhong,Huang Wei-Feng,Xiong Li,Zhou Hua-Jun,Tao Wei,Feng Zhi-Tao
Neural regeneration research
Puerarin suppresses autophagy to alleviate cerebral ischemia/reperfusion injury, and accumulating evidence indicates that the AMPK-mTOR signaling pathway regulates the activation of the autophagy pathway through the coordinated phosphorylation of ULK1. In this study, we investigated the mechanisms underlying the neuroprotective effect of puerarin and its role in modulating autophagy via the AMPK-mTOR-ULK1 signaling pathway in the rat middle cerebral artery occlusion model of cerebral ischemia/reperfusion injury. Rats were intraperitoneally injected with puerarin, 50 or 100 mg/kg, daily for 7 days. Then, 30 minutes after the final administration, rats were subjected to transient middle cerebral artery occlusion for 90 minutes. Then, after 24 hours of reperfusion, the Longa score and infarct volume were evaluated in each group. Autophagosome formation was observed by transmission electron microscopy. LC3, Beclin-1 p62, AMPK, mTOR and ULK1 protein expression levels were examined by immunofluorescence and western blot assay. Puerarin substantially reduced the Longa score and infarct volume, and it lessened autophagosome formation in the hippocampal CA1 area following cerebral ischemia/reperfusion injury in a dose-dependent manner. Pretreatment with puerarin (50 or 100 mg/kg) reduced Beclin-1 expression and the LC3-II/LC3-I ratio, as well as p-AMPK and pS317-ULK1 levels. In comparison, it increased p62 expression. Furthermore, puerarin at 100 mg/kg dramatically increased the levels of p-mTOR and pS757-ULK1 in the hippocampus on the ischemic side. Our findings suggest that puerarin alleviates autophagy by activating the APMK-mTOR-ULK1 signaling pathway. Thus, puerarin might have therapeutic potential for treating cerebral ischemia/reperfusion injury.
Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice.
Zhang Yu,Yang Xue,Ge Xuhua,Zhang Fayong
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BACKGROUND:Subarachnoid hemorrhage (SAH) results in many brain dysfunctions and the neuroprotective function of puerarin after brain damage has been demonstrated in several studies. But whether puerarin can reduce brain nerve damage after SAH is not clear.In this study, we hypothesized that puerarin had the neuroprotective effect after SAH, and this protection could be mediated by bothBcl-2/Bax/Cleaved caspase-3 and SIRT3/SOD2 apoptotic signaling pathways. METHODS:First, we used neurological score, brain water content and so on to detect the neurological deficits after SAH. Then apoptosis neuron rate was detected by TUNEL staining. Western blot was carried out to explore the alteration of Blc-2, Bax, cleaved caspase-3 and Sirt3.Also, ROS acitivity and As-lysine level of SOD2 should be detected with assays. RESULTS:We demonstrate that puerarin attenuated the neurological deficits, effectively relieves cerebral edema, and reduce BBB disruption in SAH mice.And we revealed that a reduced rate of apoptosis neuron has been found out in puerarin treatment after SAH. In addition, obviously higher ratio of Blc-2/Bax and decreased expression of cleaved caspase-3 in puerarin-treated SAH micecomparing with vehicle-treated SAH animals had been found. Furthermore, puerarin effectively reversed these alterations in expression and inhibits ROSproduction induced by SAH. Also, puerarin can increase SOD activation after SAH and protect the expression of Sirt3 after SAH. CONCLUSIONS:In coclusion, puerarin can provide potential neuroprotection from the SAH damages, and can be act as a novel therapy for SAH.
Distribution kinetics of puerarin in rat hippocampus after acute local cerebral ischemia.
Kong Hui,Zhang Guiliang,Cheng Jinjun,Shi Rongfeng,Zhang Meiling,Cao Peng,Zhao Yan,Qu Huihua,Wang Qingguo
Journal of pharmaceutical and biomedical analysis
Puerarin, isolated from the roots of Pueraria lobata, is widely used for treating cerebral ischemia in China. The time- and dose-dependent distribution characteristics of puerarin in the ischemic hippocampus are unknown. In this study, puerarin concentration was determined by an indirect competitive ELISA using anti-puerarin monoclonal antibody. Area under the curve (AUC) of puerarin (80 mg/kg) in the embolic hippocampus was higher than that in the normal hippocampus; the increase was significant only at 40 and 20 mg/kg. The maximum concentration (C) of puerarin in the embolic hippocampus was higher than that in the normal hippocampus at all doses. The increase in both AUC and C was dose-dependent. Time to reach the maximum concentration (Tmax) of puerarin in the embolic and normal hippocampus was similar. Although the mean residence time in the embolic hippocampus differed from that in the normal hippocampus at 40 and 80 mg/kg, it was higher in the embolic hippocampus than in the normal hippocampus at 20 mg/kg. This is the first study to report that the time- and dose-dependent distribution characteristics of puerarin in the normal and embolic hippocampus after middle cerebral artery occlusion in rats dictate puerarin dose and duration to treat stroke.
Puerarin provides a neuroprotection against transient cerebral ischemia by attenuating autophagy at the ischemic penumbra in neurons but not in astrocytes.
Hongyun He,Tao Guo,Pengyue Zhang,Liqiang Yang,Yihao Deng
Puerarin is an isoflavone derived from the Chinese medical herb of Radix puerariae (kudzu root), and has been widely used in the treatment for ischemic stroke in China. However, its underlying pharmacological mechanisms are still not understood. This study was to investigate the efficacy of puerarin on autophagy in the ischemic penumbra after cerebral stroke. A model of cerebral stroke in Sprague-Dawley rats was prepared by middle cerebral artery occlusion (MCAO); rats were then randomly divided into 5 groups: MCAO+Pue group (rats were treated with puerarin), MCAO+Pue+Tat-Beclin-1 group (rats were administrated with both puerarin and autophagy inducer Tat-Beclin-1), MCAO+Tat-Beclin-1 group (rats were treated with Tat-Beclin-1), MCAO+saline group (rats were administrated with the same volume of physiological saline), and sham surgery group. The autophagy levels in infarct penumbra were evaluated by western blotting, real-time PCR and immunofluorescence 14days after the insult. Meanwhile, the neurological deficit score, brain water content and infarct volume were assessed. The results illustrated that the cerebral infarct volume, cerebral edema and neurological deficiency were significantly alleviated by puerarin treatment. Western blotting and the quantitative PCR revealed that the autophagy level in the penumbra was markedly reduced by puerarin administration. However, these effects of puerarin could be counteracted by Tat-Beclin-1. Additionally, double immunofluorescence showed that neuronal autophagy was markedly attenuated by puerarin treatment, whereas astrocytic autophagy was only mildly reduced. Our study suggests that puerarin could confer a neuroprotection against cerebral ischemia, and this biological function is associated with attenuating autophagy in neurons but not in astrocytes.
Puerarin Up-regulates Methyl-CpG Binding Protein 2 Phosphorylation in Hippocampus of Vascular Dementia Rats.
Wang Hu-Qing,Zhang Meng,Zhao Jia-Xin,Wu Hai-Qin,Gao Zhen,Zhang Gui-Lian,Zhang Ru
Chinese journal of integrative medicine
OBJECTIVE:To observe the effect of puerarin on methyl-CpG binding protein 2 (MeCP2) phosphorylation (pMeCP2) in the hippocampus of a rat model of vascular dementia (VD). METHODS:Thirty-six healthy Sprague-Dawley rats were randomly assigned to the sham-operated group, dementia group and puerarintreated group using a random number table (n=12 per group). The modifified permanent bilateral common carotid artery occlusion method was used to establish the VD model. The sham-operated and dementia groups were given 2 mL/d of saline, while the puerarin-treated group was given 100 mg/(kg•d) of puerarin for 17 days. The learning and memory abilities were evaluated by the Morris water maze test. Hematoxylin-eosin staining, immunohistochemical (IHC) staining and Western blot analysis were carried out to observe changes in neuron morphology and in level of pMeCP2 in the hippocampus, respectively. RESULTS:The morphologies of rat hippocampal neurons in the puerarintreated group were markedly improved compared with the dementia group. The escape latency of the dementia group was significantly longer than the sham-operated group (P<0.05), while the puerarin-treated group was obviously shorter than the dementia group (P<0.05). Cross-platform times of the dementia group were signifificantly decreased compared with the sham-operated group (P<0.05), while the puerarin-treated group was obviously increased compared with the dementia group (P<0.05). IHC staining showed no significant difference in the number of MeCP2 positive cells among 3 groups (P>0.05). The number of pMeCP2 positive cells in the CA1 region of hippocampus in the dementia group was signifificantly increased compared with the sham-operated group, and the puerarin-treated group was signifificantly increased compared with the dementia group (both P<0.05). Western blot analysis showed no signifificant difference of MeCP2 expression among 3 groups (P>0.05). The expression of pMeCP2 in the dementia group was signifificantly increased compared with the sham-operated group, while it in the puerarin-treated group was signifificantly increased compared with the dementia group (P<0.05). CONCLUSION:Puerarin could play a role in the protection of nerve cells through up-regulating pMeCP2 in the hippocampus, improving neuron morphologies, and enhancing learning and memory ablities in a rat model of VD.
[Evaluation on safety of puerarin injection in clinical use].
Xie Xiao-Shuai,Dong Yun-Zhuo,Mu Dian-Ping,Pan Xiao-Lin,Zhang Feng-Ying
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Puerarin injection is commonly used in clinical treatment of coronary heart disease, angina pectoris, retinal artery, vein occlusion, sudden deafness and so on. This paper is aimed to evaluate the safety of puerarin injection in clinical use and explore the related factors that may cause its adverse reactions (ADRs), so as to find the warning signal of safety medication in time, put forward early warning, make early judgment and treatment, and ensure the safety of drug use. By strengthening surveillance, the best medication plan was established to prevent the occurrence of adverse reactions of puerarin injection and enhance people's awareness on the safety of puerarin injection. Database were searched to collect literature related to ADRs of puerarin injection. The data were extracted and analyzed by decision tree with treeage software and ² test was used to verify the data. A total of 62 papers involving 129 cases were included. The results showed that ADRs occurred mostly in patients aged 50-79 years, with the immune system and blood system accounting for the majority (88.3%), and ADRs occurred mostly 48 h after drug administration (61.1%). The severity of ADRs was not related to the dosage of puerarin, but it was related to the choice of the infusion solvent. In puerarin injection, most of the ADRs were moderate or severe (64.3%), 13 out of 129 cases were of death. Therefore, the indications and methods of use should be strictly controlled, and the allergic history of patients should be carefully questioned before medication to strengthen the monitoring of drug use.
Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin.
Wang Chi,Yan Muyang,Jiang Hui,Wang Qi,He Shang,Chen Jingwen,Wang Chengbin
AIM:We aim to investigate the mechanism of aquaporin 4 (AQP 4) up-regulation during high-altitude cerebral edema (HACE) in rats under hypobaric hypoxia and preventative effect of puerarin. METHODS:Rats were exposed to a hypobaric chamber with or without the preventative treatment of puerarin or dexamethasone. Morriz water maze was used to evaluate the spatial memory injury. HE staining and W/D ratio were used to evaluate edema injury. Rat astrocytes and microglia were co-cultured under the condition of hypoxia with the administration of p38 inhibitor, NF-κB inhibitor or puerarin. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF α) of cortex and culture supernatant were measured with ELISA. AQP4, phosphorylation of MAPKs, NF-κB pathway of cortex and astrocytes were measured by Western blot. KEY FINDINGS:Weakened spatial memory and cerebral edema were observed after hypobaric hypoxia exposure. AQP4, phosphorylation of NF-κB and MAPK signal pathway of cortex increased after hypoxia exposure and decreased with preventative treatment of puerarin. Hypoxia increased TNF-α and IL-6 levels in cortex and microglia and puerarin could prevent the increase of them. AQP4 of astrocytes increased after co-cultured with microglia when both were exposed to hypoxia. AQP4 showed a decrease after administered with p38 inhibitor, NF-κB inhibitor or puerarin. SIGNIFICANCE:Hypoxia triggers inflammatory response, during which AQP4 of astrocytes can be up regulated through the release of TNF-α and IL-6 from microglia. Puerarin can exert a preventative effect on the increase of AQP4 through inhibiting the release of TNF-α and phosphorylation of NF-κB, MAPK pathway.