Drug Design Development and Therapy
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2018
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IF 2.935
Ankit Parikh,Krishna Kathawala,Jintao Li,Chi Chen,Zhengnan Shan,Xia Cao,Yan-Jiang Wang,Sanjay Garg,Xin-Fu Zhou
Background Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment. Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aβ), tau phosphorylation, oxidative stress, and neuroinflammation. To enable its oral use, novel edaravone formulation (NEF) was previously developed. The aim of the present investigation was to evaluate safety and efficacy of NEF by using in vitro/in vivo disease model.Materials and methods In vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Aβ42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-β precursor protein (APP) human neuroblastoma cell line. For in vivo safety and efficacy assessment, totally seven groups of APP/PS1 (five treatment groups, one each as a basal and sham control) and one group of C57BL/6 mice as a positive control for behavior tests were used. Three groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas one group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR). Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze). For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period. Moreover, biochemical, hematological, and morphological parameters were determined.Results Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line. Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner.Conclusion Our results indicate that oral delivery of NEF holds a promise as a safe and effective therapeutic agent for AD.
研究领域:
神经科学
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药物研发
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生物化学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
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2014
·Vol. 9
·期 2
·553-558
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IF 0.941
Zhong‑Kui Xiong,Juan Lang,Gang Xu,Hai‑Yu Li,Yun Zhang,Lei Wang,Yao Su,Ai‑Jing Sun
Systemic rotenone models of Parkinson's disease (PD) are highly reproducible and may provide evidence on the pathogenesis of PD. In the present study, male Sprague‑Dawley rats (1‑year‑old) were subcutaneously administered with rotenone (1.5 mg/kg/day) for six days and observed for the following three weeks. Compared with the control rats, a significant decrease was observed in the body weight and a marked increase was observed in the areas under the behavioral scoring curves in the rotenone‑treated rats. Immunohistochemical staining revealed that the abundance of nigral tyrosine hydroxylase (TH)‑positive neurons was markedly reduced following rotenone treatment. ELISA and neurochemical assays demonstrated a significant increase in the levels of nitric oxide (NO) and NO synthase, whereas a marked decrease was observed in the thiol levels in the brains of the rotenone‑treated rats. Thus, subacute rotenone treatment was found to induce behavioral deficits and the loss of nigral TH‑positive neurons which may be associated with the excessive levels of NO in the rat brains.
研究领域:
神经科学
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药理学
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病理学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2020
·Vol. 17
·期 1
·1-13
·
IF 5.793
Bian Hetao,Wang Gaohua,Huang Junjie,Liang Liang,Zheng Yage,Wei Yanyan,Wang Hui,Xiao Ling,Wang Huiling
Background Recently, depression has been identified as a prevalent and severe mental disorder. However, the mechanisms underlying the depression risk remain elusive. The neuroinflammation and NLRP3 inflammasome activation are known to be involved in the pathology of depression. Dihydrolipoic acid (DHLA) has been reported as a strong antioxidant and exhibits anti-inflammatory properties in various diseases, albeit the direct relevance between DHLA and depression is yet unknown. The present study aimed to investigate the preventive effect and potential mechanism of DHLA in the lipopolysaccharide (LPS)-induced sickness behavior in rats. Methods Adult male Sprague–Dawley rats were utilized. LPS and DHLA were injected intraperitoneally every 2 days and daily, respectively. Fluoxetine (Flu) was injected intraperitoneally daily. PD98059, an inhibitor of ERK, was injected intraperitoneally 1 h before DHLA injection daily. Small interfering ribonucleic acid (siRNA) for nuclear factor erythroid 2-like (Nrf2) was injected into the bilateral hippocampus 14 days before the DHLA injection. Depression-like behavior tests were performed. Western blot and immunofluorescence staining detected the ERK/Nrf2/HO-1/ROS/NLRP3 pathway-related proteins. Results The DHLA and fluoxetine treatment exerted preventive effects in LPS-induced sickness behavior rats. The DHLA treatment increased the expression of ERK, Nrf2, and HO-1 but decreased the ROS generation levels and reduced the expression of NLRP3, caspase-1, and IL-1β in LPS-induced sickness behavior rats. PD98059 abolished the effects of DHLA on preventive effect as well as the levels of Nrf2 and HO-1 proteins. Similarly, Nrf2 siRNA reversed the preventive effect of DHLA administration via the decreased expression of HO-1. Conclusions These findings suggested that DHLA exerted a preventive effect via ERK/Nrf2/HO-1/ROS/NLRP3 pathway in LPS-induced sickness behavior rats. Thus, DHLA may serve as a potential therapeutic strategy for depression.
研究领域:
神经科学
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药理学
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分子生物学
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精神病学
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产品关联
DOI
PubMed
高影响因子
Toxics
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2025
·Vol. 13
·期 8
·662
·
IF 4.1
Jiahong Jiang,Qi Liu,Boxiang Zhang,Lei Zhao,Dan Xu
Sodium p-perfluorous nonenoxybenzenesulfonate (OBS) has been proposed as a substitute for perfluorooctanesulfonic acid (PFOS), yet it has garnered increasing attention due to its environmental persistence and potential toxicity. Despite these concerns, the neurotoxic mechanisms of OBS remain unclear. This study investigates and compares the neurotoxic effects and mechanisms of OBS and PFOS inCaenorhabditis elegans. L4-stage worms were exposed to OBS (0.1–100 μM) or PFOS (100 μM) for 24 h. Neurobehavioral analysis showed that OBS exposure induced concentration-dependent neurobehavioral deficits, with 100 μM OBS significantly reducing pharyngeal pumping rate (29.8%), head swing frequency (23.4%), and body bending frequency (46.6%), surpassing the effects of PFOS. Both compounds decreased the fluorescence intensity of dopaminergic, glutamatergic, and γ-aminobutyric acid neurons and downregulated neurotransmitter-associated genes. They also increased ROS generation and inhibited antioxidant gene expression. Molecular docking revealed that OBS had a stronger binding affinity to p38 MAPK key protein (PMK-1) than PFOS. OBS and PFOS upregulatedpmk-1andskn-1, modulating oxidative stress and neuronal function.pmk-1mutation differentially affected OBS-induced neurobehavioral changes and gene expression alterations. Our findings indicate that OBS exhibits stronger neurotoxicity than PFOS inCaenorhabditis elegans, mediated through the PMK-1 pathway. These results highlight the need for further investigation into the safety of OBS as a PFOS alternative.
研究领域:
毒理学
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神经科学
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环境科学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
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2025
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IF 6.9
Hu Liehai,Ren Ke,Li Yichang,Xia Yunhui,Chen Guijuan,Wang Xiaojian,Luo Chunyu,Sun Yun,Li Dongmei
Developmental exposure to environmental pollutants is increasingly recognized as a significant risk factor for autism spectrum disorder (ASD), yet the specific mechanisms by which individual toxicants contribute to this neurodevelopmental disorder remain largely unknown. Methyl ester sulfonate (MES), a widely used anionic surfactant with widespread environmental detection, lacks comprehensive evaluation for developmental neurotoxicity. Here, we exposed pregnant mice to environmentally relevant MES doses (0.06–6 mg/L) from gestational day 8.5 (GD8.5) to postnatal day 21.5 (PND21.5) and assessed their offspring for neurodevelopmental changes. Results showed dose-dependent ASD-like behavioral deficits, including impaired social interactions, heightened anxiety-like behaviors, and increased repetitive/stereotypic patterns. These behavioral anomalies were accompanied by neuropathological alterations, including blood–brain barrier disruption, neuronal loss, and reduced dendritic spine density, indicative of impaired synaptogenesis. Integrative transcriptomic analysis of hippocampal tissue revealed significant dysregulation of key pathways involved in neurodevelopment, prominently featuring the Notch/Hes signaling pathway. Molecular docking simulations suggested that MES could directly interact with Notch receptors, potentially disrupting ligand–receptor interactions. Further in vitro experimental validation demonstrated that MES exposure suppressed neural stem cell differentiation. Collectively, these findings provided evidence that early-life MES exposure acts as a neurodevelopmental toxicant by disrupting Notch/Hes signaling, thereby impairing neuronal differentiation and synaptogenesis, which underlined the observed ASD-like behavioral deficits in mice. This study offers novel mechanistic insights into how environmental factors contribute to ASD pathogenesis and highlights the need for toxicological assessment of widely distributed surfactants.
研究领域:
神经毒理学
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发育神经科学
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环境毒理学
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分子生物学
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行为神经科学
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2024
·Vol. 21
·期 1
·1-18
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IF 9.3
Su Xi,Wang Guanyu,Liu Senqi,Li Jinming,Shao Minglong,Yang Yongfeng,Song Meng,Han Yong,Li Wenqiang,Lv Luxian
Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA.
研究领域:
神经科学
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分子生物学
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行为科学
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遗传学
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2019
·Vol. 176
·期 17
·3336-3349
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IF 6.583
Hao Liu,Meng-Jing Zhao,Zi-Ying Wang,Qiao-Qiao Han,Hai-Yun Wu,Xiao-fang Mao,Yong-Xiang Wang
Background and Purpose d -Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d -amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. Experimental Approach A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. Key Results The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED 50 values of 3.9–4.5 mg·kg −1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. Conclusions and Implications Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.
研究领域:
神经科学
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药理学
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分子生物学
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神经病学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2023
·
IF 11.4
Ruiqing Zhou,Chengqing Huang,Nanxi Bi,Ling Li,Changqing Li,Xiaozhen Gu,Yang Song,Hui-Li Wang
Lead (Pb) is a widespread neurotoxic pollutant. Pb exposure is associated with mood disorders, with no well-established neural mechanisms elucidated. In the present study, we aimed to investigate whether excitatory neurons in the dentate gyrus subregion of the ventral hippocampus (vDG) played a key role in Pb-induced anxiety and depression-like behaviors. C57BL/6 mice were exposed to 100 ppm Pb starting on day 1 of pregnancy until experiments were performed using the offspring. Behavioral studies suggested that chronic Pb exposure triggered anxiety and depression-like behaviors. A combination of electrophysiological, optogenetic, and immunohistochemistry experiments was conducted. Results showed that Pb exposure resulted in excitatory neuronal hyperexcitability in vDG and that the behavioral deficits caused by Pb exposure could be rescued by inhibition of excitatory neuronal activity. Moreover, it was found that the action potential (AP) threshold of excitatory neurons was decreased by electrophysiological recordings. Our study demonstrates a significant role for excitatory neurons in vDG in Pb-induced anxiety and depression-like behaviors in mice, which is likely a result of decreased AP threshold. These outcomes can serve as an important basis for understanding mechanisms of anxiety and depression under environmental Pb exposure and help in the design of therapeutic strategies.
研究领域:
神经科学
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毒理学
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行为科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
·
IF 5.6
Ling Tang,Liyuan Wang,Feng Jin,Yuehan Hao,Tianming Zhao,Wenxu Zheng,Zhiyi He
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
研究领域:
神经科学
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
·
IF 9.4
Jichun Liu,Mingyuan Chi,Lianxin Li,Yuewen Zhang,Meng Xie
Mitochondrial dysfunction and metal ion imbalance are recognized as pathological hallmarks of Alzheimer's Disease (AD), leading to deposition of β-amyloid (Aβ) thereby and inducing neurotoxicity, activating apoptosis, eliciting oxidative stress, and ultimately leading to cognitive impairment. In this study, the red blood cell membrane (RBC) was used as a vehicle for encapsulating carbon quantum dots (CQD) and polydopamine (PDA), creating a nanocomposite (PDA-CQD/RBC). This nanocomposite was combined with near-infrared light (NIR) for AD treatment. The RBC offers anti-immunorecognition properties to evade immune clearance, PDA exhibits enzyme-mimicking activity to mitigate oxidative stress damage, and CQD acts as a chelating agent for metal ions (Cu 2+ ), effectively preventing Cu 2+ -mediated aggregation of Aβ. Furthermore, the local heating induced by near-infrared laser irradiation can dismantle the formed Aβ fibers and enhance the blood–brain barrier's permeability. Both in vitro and animal experiments have shown that PDA-CQD/RBC, in combination with NIR, mitigates neuroinflammation, and ameliorates behavioral deficits in mice. This approach targets multiple pathological pathways, surpassing the limitations of single-target treatments and enhancing therapeutic efficacy while decelerating disease progression.
研究领域:
神经科学
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纳米技术
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
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