鱼藤酮诱导的帕金森病大鼠模型中，辛酸减弱perk依赖性内质网应激信号并解决α-突触核蛋白病理问题

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-07-30 DOI:10.1016/j.neuropharm.2025.110621

Moutaz Bellah Yasser , Radwa S. Hagag , Norhan M. El-Sayed , Reem M. Hazem

{"title":"鱼藤酮诱导的帕金森病大鼠模型中，辛酸减弱perk依赖性内质网应激信号并解决α-突触核蛋白病理问题","authors":"Moutaz Bellah Yasser , Radwa S. Hagag , Norhan M. El-Sayed , Reem M. Hazem","doi":"10.1016/j.neuropharm.2025.110621","DOIUrl":null,"url":null,"abstract":"<div><div>The current study aimed to evaluate the neuroprotective potential of sinapic acid (SA) administration in alleviating Parkinson's disease (PD) features, focusing on its effects in amelioration of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) signaling, oxidative stress, and alpha-synucleinopathy in chronic ROT-induced PD rats.</div><div>PD was induced using 11 ROT injections (1.5 mg/kg/48h; s.c.). One day following the fifth ROT dose, rats started treatment with SA (10 mg/kg), SA (20 mg/kg), SA (40 mg/kg), or L-dopa/carbidopa (100/10 mg/kg) daily via oral gavage for 21 consecutive days, followed by assessment of neurobehavioral parameters and subsequent histopathological and neurochemical analyses.</div><div>Treatment with a high dose of SA amended ROT-induced locomotor deficits with significantly improved open-field ambulation, grooming, and rearing behavior, as well as increased cylinder wall forelimb placements, and prolonged rotarod fall-off latency. Additionally, SA treatment protected nigral dopaminergic neurons from ROT-induced neurodegeneration and dose-dependently preserved nigral tyrosine hydroxylase (TH) immunoexpression. Furthermore, SA treated rats showed markedly improved striatal dopamine (DA) content and diminished striatal alpha synuclein (α-Syn) overexpression. Additionally, SA treatment provided antioxidant properties as evidenced by improved striatal GSH/SOD/Catalase and suppressed MDA levels. Notably, SA administration resulted in significant, dose-dependent attenuation of ER stress sensors PERK, eIF2α, CHOP/GADD135, IRE1α, and ATF6 signaling.</div><div>These findings provide novel <em>in vivo</em> insights into SA's beneficial neuroprotective properties in amelioration of ROT-induced ER stress via modulation of all three UPR branches, particularly the PERK/eIF2α/CHOP signaling axis, and establishes SA as a promising neurotherapeutic candidate for possible management of PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110621"},"PeriodicalIF":4.6000,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Sinapic acid attenuates PERK-dependent ER stress signaling and resolves α-synuclein pathology in rotenone-induced Parkinson's disease rat model\",\"authors\":\"Moutaz Bellah Yasser , Radwa S. Hagag , Norhan M. El-Sayed , Reem M. Hazem\",\"doi\":\"10.1016/j.neuropharm.2025.110621\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The current study aimed to evaluate the neuroprotective potential of sinapic acid (SA) administration in alleviating Parkinson's disease (PD) features, focusing on its effects in amelioration of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) signaling, oxidative stress, and alpha-synucleinopathy in chronic ROT-induced PD rats.</div><div>PD was induced using 11 ROT injections (1.5 mg/kg/48h; s.c.). One day following the fifth ROT dose, rats started treatment with SA (10 mg/kg), SA (20 mg/kg), SA (40 mg/kg), or L-dopa/carbidopa (100/10 mg/kg) daily via oral gavage for 21 consecutive days, followed by assessment of neurobehavioral parameters and subsequent histopathological and neurochemical analyses.</div><div>Treatment with a high dose of SA amended ROT-induced locomotor deficits with significantly improved open-field ambulation, grooming, and rearing behavior, as well as increased cylinder wall forelimb placements, and prolonged rotarod fall-off latency. Additionally, SA treatment protected nigral dopaminergic neurons from ROT-induced neurodegeneration and dose-dependently preserved nigral tyrosine hydroxylase (TH) immunoexpression. Furthermore, SA treated rats showed markedly improved striatal dopamine (DA) content and diminished striatal alpha synuclein (α-Syn) overexpression. Additionally, SA treatment provided antioxidant properties as evidenced by improved striatal GSH/SOD/Catalase and suppressed MDA levels. Notably, SA administration resulted in significant, dose-dependent attenuation of ER stress sensors PERK, eIF2α, CHOP/GADD135, IRE1α, and ATF6 signaling.</div><div>These findings provide novel <em>in vivo</em> insights into SA's beneficial neuroprotective properties in amelioration of ROT-induced ER stress via modulation of all three UPR branches, particularly the PERK/eIF2α/CHOP signaling axis, and establishes SA as a promising neurotherapeutic candidate for possible management of PD.</div></div>\",\"PeriodicalId\":19139,\"journal\":{\"name\":\"Neuropharmacology\",\"volume\":\"279 \",\"pages\":\"Article 110621\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-07-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuropharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0028390825003296\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390825003296","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

摘要

本研究旨在评估sinapic acid （SA）给药在缓解帕金森病（PD）特征方面的神经保护潜力，重点关注其在改善慢性rot诱导的PD大鼠内质网（ER）应激介导的未折叠蛋白反应（UPR）信号、氧化应激和α -突触核蛋白病中的作用。采用11次ROT (1.5 mg/kg/48h；南卡罗来纳州)。在第5次ROT给药后第1天，大鼠开始每天口服SA （10 mg/kg）、SA （20 mg/kg）、SA （40 mg/kg）或左旋多巴/卡比多巴（100/10 mg/kg）治疗，连续21天，随后评估神经行为参数，随后进行组织病理学和神经化学分析。用高剂量SA治疗可以改善rot诱导的运动缺陷，显著改善露天活动、修饰和饲养行为，增加前肢圆柱体壁放置，延长旋转杆脱落潜伏期。此外，SA处理保护黑质多巴胺能神经元免受rot诱导的神经变性和剂量依赖性保存的黑质酪氨酸羟化酶（TH）免疫表达。此外，SA处理大鼠纹状体多巴胺（DA）含量显著提高，纹状体α-突触核蛋白（α-Syn）过表达减少。此外，通过改善纹状体GSH/SOD/过氧化氢酶和抑制MDA水平，SA处理具有抗氧化性能。值得注意的是，SA给药导致内质网应激传感器PERK、eIF2α、CHOP/GADD135、IRE1α和ATF6信号的明显剂量依赖性衰减。这些发现为SA通过调节所有三个UPR分支，特别是PERK/eIF2α/CHOP信号轴，改善rot诱导的内质网应激的有益神经保护特性提供了新的体内见解，并确立了SA作为可能治疗PD的有前途的神经治疗候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Sinapic acid attenuates PERK-dependent ER stress signaling and resolves α-synuclein pathology in rotenone-induced Parkinson's disease rat model

The current study aimed to evaluate the neuroprotective potential of sinapic acid (SA) administration in alleviating Parkinson's disease (PD) features, focusing on its effects in amelioration of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) signaling, oxidative stress, and alpha-synucleinopathy in chronic ROT-induced PD rats.

PD was induced using 11 ROT injections (1.5 mg/kg/48h; s.c.). One day following the fifth ROT dose, rats started treatment with SA (10 mg/kg), SA (20 mg/kg), SA (40 mg/kg), or L-dopa/carbidopa (100/10 mg/kg) daily via oral gavage for 21 consecutive days, followed by assessment of neurobehavioral parameters and subsequent histopathological and neurochemical analyses.

Treatment with a high dose of SA amended ROT-induced locomotor deficits with significantly improved open-field ambulation, grooming, and rearing behavior, as well as increased cylinder wall forelimb placements, and prolonged rotarod fall-off latency. Additionally, SA treatment protected nigral dopaminergic neurons from ROT-induced neurodegeneration and dose-dependently preserved nigral tyrosine hydroxylase (TH) immunoexpression. Furthermore, SA treated rats showed markedly improved striatal dopamine (DA) content and diminished striatal alpha synuclein (α-Syn) overexpression. Additionally, SA treatment provided antioxidant properties as evidenced by improved striatal GSH/SOD/Catalase and suppressed MDA levels. Notably, SA administration resulted in significant, dose-dependent attenuation of ER stress sensors PERK, eIF2α, CHOP/GADD135, IRE1α, and ATF6 signaling.

These findings provide novel in vivo insights into SA's beneficial neuroprotective properties in amelioration of ROT-induced ER stress via modulation of all three UPR branches, particularly the PERK/eIF2α/CHOP signaling axis, and establishes SA as a promising neurotherapeutic candidate for possible management of PD.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).