EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Junjie Huang,Jiahao Zhu,Huijun Zheng,Enhui Zhu,Chenqi Yang,Liqin Ying,Yucong Zhou,Hao Liu
The neuroprotective effect of DAAOi is associated with increased levels of its substrate, D-Serine. • D-Serine can ameliorate cognitive and behavioral deficits in MCAO rats. • D-Serine may exert its neuroprotective effect by promoting the D-Serine/GluN2A/BDNF signaling pathway. To investigate the mechanisms of D-Amino acid oxidase inhibitor (DAAOi) in ameliorating cerebral ischemia-reperfusion (I/R) injury and the underlying neuroprotective effect of substrate D-Serine. A middle cerebral artery occlusion (MCAO) rat model and an oxygen-glucose deprivation (OGD)-induced HT22 cell model were used to mimic ischemic stroke. The modified Neurological Severity Scores (mNSS) and 2, 3, 5-triphenyltetrazolium chloride staining were applied to assess neurological behavioral scores and cerebral infarct area, respectively. The effects of DAAOi 4H-Furo[3,2-b]pyrrole-5- carboxylic acid (SUN) and D-Serine intervention on cognitive and behavioral functions in MCAO rats were evaluated by using the Y-maze and Novel Object Recognition Test (NORT). Intracerebral stereotaxic injection of Compound SUN and D-Serine (0.21 mg, 1.05 mg, 2.1 mg) significantly reduced cerebral infarct area, indicating that DAAOi might improve cerebral I/R injury by elevating D-Serine levels. Similarly, D-Serine significantly enhanced cognitive and behavioral performance in MCAO rats (mNSS: improved by 2.3 scores; Y-maze: spontaneous alternation rate increased by 14.76%; NORT: recognition index improved by 12.28%). D-Serine pretreatment (10 μM-10 mM) dose-dependently increased the viability of HT22 cells subjected to OGD. In both in vitro and in vivo models, D-Serine significantly increased the protein level of N-methyl-D-aspartate receptor subunit 2A (GluN2A). Additionally, D-Serine promoted the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein-95 but inhibited the apoptosis-related p38 MAPK phosphorylation. This study demonstrated that the neuroprotective effect of DAAOi was at least partly mediated by elevating cerebral D-Serine levels, which regulated the GluN2A/BDNF axis to enhance synaptic plasticity and cognitive function. Download: Download high-res image (323KB) Download: Download full-size image
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
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2023
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IF 4.7
Rongjun Liu,Daofan Sun,Xiuzhong Xing,Qingge Chen,Bo Lu,Bo Meng,Hui Yuan,Lan Mo,Liufang Sheng,Jinwei Zheng,Qiusheng Wang,Junping Chen,Xiaowei Chen
The comorbidity of pain and depression is frequently observed in patients suffering from chronic pain and depression. However, the comorbid mechanism is not well elucidated and the therapeutic medication is still inadequate. Oxytocin is a neuropeptide synthesized in the hypothalamus. It has been reported to relieve chronic pain and depressive symptoms. However, the analgesic action and mechanisms of oxytocin have mainly been investigated using peripheral or spinal administration. Because of the advantage of intranasal delivery of oxytocin in crossing the blood-brain barrier, we investigated the effect of intranasal application of oxytocin on neuropathic pain and comorbid depressive symptoms in both female and male mice. In female and male mice receiving spared nerve injury (SNI) surgery, intranasal oxytocin (2.4 μg, daily for 28 days) attenuated depression-like behavior , but did not alleviate mechanical hyperalgesia . Intranasal oxytocin not only inhibited the activation of microglia and astrocytes, but also increased the downregulated oxytocin receptor (OTR) expression, reversed the elevated GluN2A, and restored the decreased BDNF expression in the hippocampus . SNI also decreased OTR expression in the spinal cord and increased spinal GluN2A and BDNF. However, intranasal oxytocin treatment did not change the expression levels of OTR, GluN2A, or BDNF in the spinal cord of neuropathic mice. The results suggest that the oxytocin signaling in the hippocampus is involved in the comorbidity of pain and depression, and intranasal oxytocin may have the potential to treat depressive symptoms in neuropathic pain patients.
研究领域:
神经科学
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疼痛管理
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药理学
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行为科学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2021
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IF 4.36
Fengming Shen,Zhujin Song,Pan Xie,Lei Li,Bin Wang,Daiyin Peng,Guoqi Zhu
Ethnopharmacological relevance According to traditional Chinese medicine (TCM) theory ( Yi Xue Zheng Zhuan ), the main factors associated with the pathogenesis of depression are deficiencies relating to five zang organs, Qi, and blood. Polygonatum sibiricum F. Delaroche (PS), which may avert these pathological changes, has been used in a variety of formulas to treat depression. However, the effects and mechanism of action of PS, alone, and especially those of its main active component PS polysaccharide (PSP), on depression remain unexplored. Aim of the study To determine the effects of PSP on depression-like behaviors and to elucidate its mechanism of action. Methods PSP was isolated from dried PS rhizomes and qualified using transmission electron microscopy and Fourier transform infrared spectroscopy . Lipopolysaccharide (LPS) and chronic unpredictable mild stress (CUMS)-induced depression models were used to evaluate the antidepressive effects of PSP. Veinal blood and brain tissue were collected to determine the levels of hippocampal 5-HT, serum cortisol (CORT), brain and serum cytokines, and hippocampal oxidation-related indicators. The protein expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), glial fibrillary acidic protein (GFAP), phosphorylated protein kinase B (p-Akt), phosphorylation of the mammalian target of rapamycin (mTOR), caspase-3, GluA1 and GluA2, and GluN2A and GluN2B were determined using western blotting and immunofluorescence. Nissl staining was performed to detect histopathological changes in brain tissues. Results Injection of LPS ( i.p. ) induced depression-like behaviors, reduced the level of hippocampal 5-HT, increased the serum CORT level and hippocampal oxidative stress (ROS), and prompted the activation of ERK1/2, NF-κB, and GFAP and an inflammatory response. Conversely, PSP administration reduced these changes and prevented depression-like behaviors. PSP administration also promoted hippocampal expression of p-Akt, p-mTOR, GluA1, and GluA2; reduced the expression of caspase-3, GluN2A, and GluN2B; and prohibited the loss of granular cells in the DG region. Conclusion These results indicate that PSP prevents depression-like behaviors, and synaptic and neuronal damage probably by reducing ROS/HPA axis hyperfunction and the inflammatory response.
研究领域:
药理学
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神经科学
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中医
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分子生物学
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PubMed
高影响因子
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