摘要：
Parkinson’s disease (PD) is characterized by α-synuclein accumulation, dopaminergic neuron loss and inflammation. α-Synuclein can be secreted by neurons and activate microglia to different degrees. Excessive microglial activation can increase the production of tumor necrosis factor alpha (TNF-α), interleukin-1-β (IL-1β), interleukin-6 (IL-6), interferon-γ (INF-γ), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and nitric oxide (NO), and can also enhance microglial phagocytosis and migration as well as lymphocyte infiltration. Pathological α-synuclein and microglial activation can potentiate each other, leading to the loss of dopaminergic neurons and accelerated PD degeneration. This review will mainly describe the profiles of α-synuclein-activated microglia, with particular emphasis on the signaling cascades involved in this process.
作者机构：
湖南中医药大学药学院,湖南 长沙 410208;中国医学科学院神经科学中心,中国医学科学院北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京 100050;[朱天碧; 罗飘; 陈乃宏; 楚世峰] College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China, State Key Lab of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100050, China
作者机构：
[姜懿纳; 石雅宁; 罗林明; 詹济华; Qin L.] College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China;Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China;[陈乃宏] College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
通讯机构：
[Chen, N.-H.] C;College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
摘要：
IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K-dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X-interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke.
摘要：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP-treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg·kg~(-1)·d~(-1), ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg~(-1)·d~(-1)),pramipexole (3 mg·kg~(-1)·d~(-1)), or medopar (100 mg·kg~(-1)·d~(-1)) for 18 days. Behavioral performance was assessed in the open field test, pole test and rota rod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the a-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, a-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.
作者机构：
[Yang, Peng-Fei; Song, Xiu-Yun; Zhang, Shuai; Chen, Nai-Hong; Xia, Cong-Yuan; Zuo, Wei] Chinese Acad Med Sci, Dept State Key Lab Bioact Subst & Funct Nat Med, Peking Union Med Coll, Inst Mat Med, Beijing 100050, Peoples R China.;[Yang, Peng-Fei; Song, Xiu-Yun; Zhang, Shuai; Chen, Nai-Hong; Xia, Cong-Yuan; Zuo, Wei] Chinese Acad Med Sci, Peking Union Med Coll, Neurosci Ctr, Beijing 100050, Peoples R China.;[Ai, Qi-Di; Zeng, Ting; Chen, Nai-Hong] Hunan Univ Chinese Med, Coll Pharm, Changsha, Hunan, Peoples R China.;[He, Xin; Liu, Dan-Dan] Tianjin Univ Tradit Chinese Med, Tianjin, Peoples R China.
通讯机构：
[Chen, Nai-Hong] C;[Chen, Nai-Hong] H;Chinese Acad Med Sci, Dept State Key Lab Bioact Subst & Funct Nat Med, Peking Union Med Coll, Inst Mat Med, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Peking Union Med Coll, Neurosci Ctr, Beijing 100050, Peoples R China.;Hunan Univ Chinese Med, Coll Pharm, Changsha, Hunan, Peoples R China.
摘要：
Strokes are the leading cause of death and disability all over the world, however, there are few satisfactory therapies. IMM-H004 citrate (004), 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin, is a coumarin derivative which has potential therapeutic effects in brain ischemia with ambiguous mechanisms. We aim to study the anti-brain ischemia effect and mechanism of 004 in spontaneously hypertensive (SHR) rats. Adult male Wistar-Kyoto (WKY) rats and SHR rats were subjected to 24 h reperfusion after transient middle cerebral artery occlusion (tMCAO) for 1 h and were intravenously injected with 004 or Edaravone at the time of reperfusion. Behavioral scores, magnetic resonance imaging (MRI) and TTC staining were used to test the therapeutic effect of 004. To study the mechanism, the infiltration of leukocytes, the activation of microglia, blood viscosity, the expression of VCAM-1, MMPs and proteins involved in the MAPK/NF-κB pathway were researched. The results indicated that tMCAO/R induced serious injury, while 004 significantly alleviated the infarct volume and improved neurological deficits. 004 improved inflammatory processes, such as the enhancement of blood viscosity, expression of VCAM-1 and MMP2, release of TNF-α, IL-1β, IL-6 and IL-23, phosphorylation of JNK and p38 and translocation of NF-κB, which play crucial roles in brain I/R in SHR rats. An in vitro study also proved that 004 regulated JNK and NF-κB pathways and decreased the expression of VCAM-1, which eventually led to the suppression of neuroinflammation.
摘要：
Ethnopharmacological relevance: Da-Bu-Yin-Wan (DBYW), a historically traditional Chinese medicine formula, was originally defined over 600 years ago. In recent decades, DBYW was clinically employed to treat Parkinson's disease (PD). Aim of the study: To explore the underlying mechanism of DBYW on mitochondrial function, we investigated the effect of DBYW on mitochondrial function from the perspectives of DJ-1 and Akt signaling. Materials and methods: Human derived neuroblastoma SH-SY5Y cells were transiently transfected with the plasmid pcDNA3-Flag-DJ-1 aimed to overexpress the DJ-1 protein. Transfected cells were treated with 1-methyl-4-phenylpyridinium (MPP+), a PD-related mitochondrial complex I inhibitor, in the absence and presence of DBYW. The cell viability was assessed by Cell Counting Kit-8 assay. The protein expressions of DJ-1 and Akt signaling were examined by western blotting. The mitochondrial mass was evaluated by confocal fluorescence microscopy. The mitochondrial complex I activity and cellular ATP content were measured by commercial kits. Results: Transfection with pcDNA3-Flag-DJ-1 decreased the MPP-induced toxicity and overexpressed the DJ-1. In DJ-1 overexpressed cells, the mitochondrial mass was raised, mitochondrial complex I activity was improved, and cellular ATP content was increased. In addition, overexpression of DJ-1 augmented the Akt phosphorylation on threonine 308 and serine 473. Moreover, DBYW promoted the above effects in DJ-1 expressed cells. Conclusions: These data suggest that DJ-1 protects the mitochondria] function by medicating Akt phosphorylation in MPP+-treated SH-SY5Y cells. Moreover, DBYW enhances the protective effect of DJ-1 medicated Akt phosphorylation on mitochondrial function. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
作者机构：
[张钊] Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100050, China;College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China;[陈乃宏] Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100050, China, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China
通讯机构：
[Chen, N.-H.] I;Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
摘要：
Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors. (C) 2015 Elsevier Inc. All rights reserved.
摘要：
Parkinson's disease (PD) is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of aggregated alpha-synuclein in specific central nervous system (CNS) regions. Disease development is attributed to alpha-synuclein abnormalities, particularly aggregation and phosphorylation. The ginsenoside Rg1, an active component of ginseng, possesses neuroprotective and anti-inflammatory effects. The purpose of the present study was to evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms. Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal ultrastructure changes in the SNpc. Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties. Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related alpha-synuclein in the SNpc. In conclusion, Rg1 protects dopaminergic neurons, most likely by reducing aberrant alpha-synuclein-mediated neuroinflammation, and holds promise for PD therapeutics. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
作者机构：
School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China;[娄钰霞] Tianjin University of Chinese Medicine, Tianjin, 300193, China;[张钊] Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China;[陈乃宏; 姜懿纳] School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
