Advanced Science
·
2025
·
IF 14.1
Jin-Hui Shi,Qi-Long Tang,Jin-Hong Wang,Yan-Lan Long,Sai-Feng Zhao,Zhen Zhao,Wan-Ting Xie,Zi-Ming Li,Hao-Ming Lu,Tian-Xiao Gao,Zhen-Zhen Fang,Ti Zhou,Bo-Xing Li,Xia Yang,Guo-Quan Gao,Wei-Wei Qi
Maintenance of glutamate homeostasis is essential for synaptic plasticity and cognition. Disrupted glutamate-glutamine cycling causes chronic excitotoxicity, a key driver of cognitive deficits in Alzheimer's disease (AD), though regulatory mechanisms remain unclear. Pigment epithelium-derived factor (PEDF), a neuroprotective protein declining with age, is demonstrated here to play a novel role in synaptic glutamate clearance. Analysis of peripheral blood samples from 19 patients with AD and 75 non-dementia control subjects revealed lower levels of PEDF in patients, and loss of PEDF correlates with cognitive decline. PEDF-deficient mice exhibit defective learning and memory, and higher susceptibility to AD. Furthermore, PEDF deficiency impaired synaptic plasticity and dendritic spine morphology. Mechanistically, PEDF inhibits ubiquitin-proteasome-dependent degradation of astrocytic glutamate transporter-1 (GLT-1) and normally guarantees elimination of synaptic glutamate by modulating the protein kinase C signaling pathway. Strikingly, restoring PEDF rescued cognitive deficits in a mouse model of AD, and upregulation of GLT-1 rescued cognitive impairment in PEDF-deficient mice. Collectively, these findings reveal PEDF is a physiologic regulator of synaptic glutamate homeostasis. Targeting PEDF deficiency-induced neural impairment may provide a novel avenue for the development of new therapeutic applications for neurodegenerative diseases associated with glutamate-induced excitotoxicity.
研究领域:
神经生物学
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分子医学
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神经退行性疾病
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转化神经科学
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信号转导
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老年医学
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代谢与营养
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Bike Zhang,Dan Su,Yonggui Song,Huizhen Li,Changlian Chen,Liangliang Liao,Hongjie Zhang,Jian Luo,Ming Yang,Genhua Zhu,Zhifu Ai
Phytochemical investigation of the volatile oil of Yueju (YJVO) and its constituent herbs induced the detection of 52 compounds in YJVO, mainly monoterpenes and sesquiterpenes as well as a small amount of aromatic and aliphatic compounds. 5 of these compounds were found only in the YJVO instead of the volatile oil of its constituent herbs. The anti-depressant effect of YJVO was proved by behavioral tests in chronic unpredictable mild stress (CUMS) mice. An acute oral toxicity evaluation determined the LD 50 of YJVO was 5.780 mL/kg. Doppler ultrasound and laser speckle imaging have detected that the YJVO could improve depression-related cerebral blood flow. In addition, related neurotransmitters and proteins were analyzed through targeted metabolomics and immunofluorescence. The potential antidepressant mechanisms of YJVO related to significantly decreasing Glu in CUMS mice by up-regulating the ERK/AKT-mediated expression of GLT-1.
研究领域:
药理学
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神经科学
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植物化学
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行为科学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Yuhang Ge,Fei Zhen,Ziqi Liu,Zhaowei Feng,Gui Wang,Chu Zhang,Xingqi Wang,Ying Sun,Xiaohui Zheng,Yajun Bai,Ruiqin Yao
Preterm white matter injury (PWMI) is the most common form of brain damage in premature infants caused by hypoxia-ischemia (HI), inflammation, or excitotoxicity. It is characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination. Our previous study confirmed that alpha-asarone (α-asaronol), a major compound isolated from the Chinese medicinal herb Acorus gramineus by our lab, could alleviate neuronal overexcitation and improve the cognitive function of aged rats. In the present study, we investigated the effect and mechanism of α-asaronol on myelination in a rat model of PWMI induced by HI. Notably, α-asaronol promoted OPC differentiation and myelination in the corpus callosum of PWMI rats. Meanwhile, the concentration of glutamate was significantly decreased, and the levels of PPARγ and glutamate transporter 1 (GLT-1) were increased by α-asaronol treatment. In vitro, it was also confirmed that α-asaronol increased GLT-1 expression and recruitment of the PPARγ coactivator PCG-1a in astrocytes under oxygen and glucose deprivation (OGD) conditions. The PPARγ inhibitor GW9662 significantly reversed the effect of α-asaronol on GLT-1 expression and PCG-1a recruitment. Interestingly, the conditioned medium from α-asaronol-treated astrocytes decreased the number of OPCs and increased the number of mature oligodendrocytes. These results suggest that α-asaronol can promote OPC differentiation and relieve dysmyelination by regulating glutamate levels via astrocyte PPARγ-GLT-1 signaling. Although whether α -asaronol binds to PPARγ directly or indirectly is not investigated here, this study still indicates that α -asaronol may be a promising small molecular drug for the treatment of myelin-related diseases.
研究领域:
神经科学
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药理学
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儿科
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分子生物学
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DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2022
·Vol. 37
·期 8
·2883-2901
·
IF 3.655
Jiang Chuan,Wang Hua,Qi Jiaying,Li Jinghan,He Qianqian,Wang Chaonan,Gao Yonggang
Cherry leaves ( Prunus pseudocerasus Lindl. [Rosaceae] ), a traditional Chinese herbal medicine, can regulate the factors closely related to depression including inflammatory cytokines, oxidative stress and blood glucose level. However, the antidepressant effects of cherry leaves and underlying neuromodulatory mechanisms remain relatively have not been elucidated explicitly. The present study investigated the antidepressant effects of cherry leaf decoction (CLD). The underlying neuromodulatory mechanism was explored by examining the glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) metabolic loop. The chronic unpredictable mild stress (CUMS) rodent model was used in this study. The main flavonoids components of CLD were identified using high-performance liquid chromatography (HPLC). The antidepressant effects of CLD were assessed throughout behavioural tests including the bodyweight, sucrose preference test (SPT), forced swimming test (FPT) and tail suspension test (TST). Moreover, The baseline levels of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were quantified. The expression of proteins integrally involved in the Glu/GABA-Gln metabolic loop were observed and quantified by Western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. This study found that CLD ameliorated depressive-like behaviours induced by CUMS. The increase of serum ACTH and CORT baseline levels induced by CUMS was also reversed after CLD intervention. Furthermore, CUMS reduced the expression of GAD65, GAD67, GLT-1, GS and GABA A and increased NMDAR1 levels in the rat hippocampus, which was normalized by CLD treatment. The findings demonstrated that CLD could ameliorate the depression-like behaviours induced by CUMS, potentially through the inhibition of hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and the regulation of Glu/GABA-Gln metabolic loop. Graphical abstract
研究领域:
药理学
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神经科学
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传统中药
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）