摘要：
The present study investigated the neuroprotective effects of Forsythia suspense extract in a rotenone induced neurotoxic model. FS8, one of the herbal extracts, markedly protected PC12 cells against rotenone toxicity and was selected for the in vivo study. Gavage administration of FS8 (50 and 200 mg/kg, but not 10 mg/kg) for 25 days significantly improved the behavior function, decreased the loss of dopaminergic neurons in substantia nigra (SN), and maintained the level of dopamine in striatum after unilateral infusion of rotenone in SN. Wherein, the protective effects of FS8 at the dose of 200 mg/kg were better than selegiline. Further study indicated the excellent antioxidant activity of FS8 on the 5th and 21st days after intranigral injection of rotenone. Moreover, FS8 could inhibit microglia activity and accumulation in SN, and obviously decreased the expression of pro-inflammatory molecules (IL-6, TNF-alpha, iNOS and COX-2), which indicated the anti-inflammatory effects of FS8. In the PI3K/Akt/NF-kappa B and MAPK pathways, FS8 significantly down-regulated the protein expression of p-PI3K, p-Akt, p-I kappa B, p-P65, cleaved Caspase 8, p-p38 and p-JNK but not p-mTOR, cleaved Caspase 3 and p-ERK Therefore, FS8 protected dopamine neurons against rotenone toxicity via antioxidant and anti-inflammatory effects, which suggested the promising application of FS8 in the prevention and treatment of Parkinson disease. (C) 2015 Elsevier Inc. All rights reserved.
摘要：
Mutations, duplication and triplication of alpha-synuclein genes are linked to familial Parkinson's disease (PD), and aggregation of alpha-synuclein (alpha-syn) in Lewy bodies (LB) is involved in the pathogenesis of the disease. The targeted overexpression of alpha-syn in the substantia nigra (SN) mediated by viral vectors may provide a better alternative to recapitulate the neurodegenerative features of PD. Therefore, we overexpressed human wild-type alpha-syn using rAAV2/1 vectors in the bilateral SN of mouse and examined the effects for up to 12 weeks. Delivery of rAAV-2/1-alpha-syn caused significant nigrostriatal degeneration including appearance of dystrophic striatal neurites, loss of nigral dopaminergic (DA) neurons and dissolving nigral neuron bodies in a time-dependent manner. In addition, the alpha-syn overexpressed mice also developed significant deficits in motor function at 12 weeks when the loss of DA neurons exceeded a threshold of 50%. To investigate the sensitivity to neurotoxins in mice overexpressing alpha-syn, we performed an MPTP treatment with the subacute regimen 8 weeks after rAAV injection. The impact of the combined genetic and environmental insults on DA neuronal loss, striatal dopamine depletion, dopamine turnover and motor dysfunction was markedly greater than that of either alone. Moreover, we observed increased phosphorylation (S129), accumulation and nuclear distribution of alpha-syn after the combined insults. In summary, these results reveal that the overexpressed alpha-syn induces progressive nigrostriatal degeneration and increases the susceptibility of DA neurons to MPTP. Therefore, the targeted overexpression of alpha-syn and the combination with environmental toxins may provide valuable models for understanding PD pathogenesis and developing related therapies.
作者机构：
[陆国寿; Zeng X.-B.; 林霄; 何飞; 黄周锋; 韦桂宁; 卢文杰; 韦宝伟; 苏华; 谭晓] Dept. of Pharmaocology, Guangxi Institute of Chinese Medicine and Pharmaceutical Science, Naming, 530022, China;[楚世峰] TCM School, Hunan University of Chinese Medicine, Changsha, 410208, China;[苏启表] College of Health Science, Guangdong Pharmaceutical University, Guangzhou, 510006, China;[陈乃宏] Pharmacy College, Hunan University of Chinese Medicine, Changsha, 410208, China
作者机构：
[Liu, Yan; Song, Lian-Kun; Sun, Jian-Dong; Chen, Nai-Hong; Li, Jing; Yuan, Yu-He] Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Liu, Yan; Song, Lian-Kun; Sun, Jian-Dong; Chen, Nai-Hong; Li, Jing; Yuan, Yu-He] Peking Union Med Coll, Beijing 100050, Peoples R China.;[Chen, Nai-Hong; Chu, Shi-Feng] Hunan Univ Chinese Med, Changsha 410208, Hunan, Peoples R China.;[Chen, Nai-Hong] Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, 1 Xiannongtan St, Beijing 100050, Peoples R China.
通讯机构：
[Chen, Nai-Hong] C;Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, 1 Xiannongtan St, Beijing 100050, Peoples R China.
关键词：
Parkinson's disease;Rotenone;Environmental exposure;Animal model;alpha-Synuclein;Motor and nonmotor symptoms
摘要：
Epidemiological studies suggest an association between pesticides and the incidence of Parkinson's disease (PD). Individuals are likely to be exposed to numerous natural or synthetic environmental agents by ingestion, inhalation, or skin contact. Here, we describe a novel environment-contact administration of rotenone model, in which male C57BL/6 mice (15 per group per time-point) were placed in one bedding-free, rotenone-applied cage for 2 h every day over a period of 2-6 weeks, mimicking the common ways a person may be exposed to pesticides. Our results showed that rotenone exposure had no detrimental effect on body weights of mice during 6 weeks, nor did it cause systemic toxicity (HPLC analysis of rotenone in blood and brain, as well as complex I activity measurements in brain and muscle), but it caused significant impairments in motor function (open field test, pole test, and rotarod test) from 4 weeks that were responsive to apomorphine. Accordingly, rotenone caused significant dopamine depletion from the striatum (HPLC analysis), nigrostriatal degeneration (quantitative tyrosine hydroxylase immunohistochemistry and western blot), and accumulation of a-synuclein in the substantia nigra and striatum (alpha-synuclein immunohistochemistry) in a time-dependent manner. In addition, rotenone-exposed mice also developed deficits in gastrointestinal and olfactory function (fecal pellet output and buried food pellet test) prior to the motor dysfunction. Furthermore, we observed that alpha-synuclein accumulated in the anterior olfactory nucleus and the enteric nervous system at 2 weeks. In summary, this novel rotenone model was able to reproduce many key aspects of PD progression. Therefore, it provides new insight into how environmental factors could trigger PD and provides a useful tool for studying PD pathogenesis and testing neuroprotective strategies. (C) 2015 Elsevier B.V. All rights reserved.
作者机构：
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia;Hunan University of Chinese Medicine,Changsha,China
摘要：
Depression is a leading cause of disability worldwide.However the biological and molecular mechanisms underlying this disorder remain to be unknown.Stress is a disposing factor in the development of depression, which could lead to HPA axis activation and the release of glucocorticoids.Glucocorticoids have two receptors, one is GR, the other is MR.Despite the fact that GR has been extensively studied, there is increasingly awareness that MR has a crucial role in the development of depression.This review summarizes how the MR plays a role in the pathophysiology of depression in HPA axis regulation, inflammation, neurogenesis as well as stressrelated behaviors.Considering that the research about MR in the development of depression is limited, further investigation of MR is needed for better understanding of this disease, which could contribute to the prevention and treatment of depressive disorder.
摘要：
Resident microglia are the major immune cells in the brain, acting as the first defense of the central nervous system. Following cerebral ischemia, microglia respond to this injury at first and transform from surveying microglia to active state. The activated microglia play a dual role in the ischemic injury, due to distinct microglia phenotypes, including deleterious M1 and neuroprotective M2. However, microglia show transient M2 phenotype followed by a shift to M1. The high ratio of M1 to M2 is significantly related to ischemic injury. Many signal pathways participate in the alternation of microglial phenotype, presenting potential therapeutic targets for selectively modulating M2 polarization of microglia. In this review, we discuss how the M2 phenotype mediates neuroprotective effects and summarize the alternation of signaling cascades that control microglial phenotype after ischemic stroke. (C) 2015 Elsevier B.V. All rights reserved.
