Neuroprotective effects of candesartan in 3-nitropropionic acid-induced Huntington's disease: modulation of angiotensin and CREB/BDNF/PGC1-α signaling.

IF 5.3 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2025-09-16 DOI:10.1007/s10787-025-01889-6

Ali M Elgindy, Ahmed M Atwa, El-Sayed E El-Awady, Norhan M El-Sayed, Naglaa F El-Orabi

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引用次数: 0

Abstract

Renin-Angiotensin System has been implicated in neurodegenerative diseases such as Huntington's (HD). It is made up of two axes: one is the Angiotensin II Type 1 receptor (AT1R) or Angiotensin II Type 2 receptor (AT2R), while the other is angiotensin-(1-7) [Ang-(1-7)], and Mas receptor; the latter has reported developing a neuroprotective effect; oppositely, AT1R activation has been linked to neurodegenerative diseases. This study aims to elucidate the potential neuroprotective effect of Candesartan (Cand) an AT1R blocker in mitigating neuronal degeneration caused by 3-Nitropropionic acid (3NP) induced HD by revealing the prospective role of Ang II/AT2R/Ang-(1-7)/Mas receptor, CREB/BDNF/PGC1-α besides JNK/c-Jun trajectories, as well as the anti-apoptotic survivin. HD was induced by 3NP (10 mg/kg) for 14 days. Rats received Candesartan (2.5 or 5 mg/kg) for 14 days, after which brain and striatum were isolated for the histopathological, immunohistochemical, and biochemical analysis. Cand displayed significant improvement in the rats' behavioral tests, enhancing their memory, motor, and cognitive functions induced by 3NP, which was confirmed by the striatal histopathological and immunohistochemical examination of the GFAP. In addition, Cand activated the Ang II/AT2R/Ang-(1-7)/Mas receptor axis. Moreover, Cand stimulated the production of striatal neurotrophic proteins CREB/BDNF/PGC1-α which in turn decreased the levels of inflammatory mediators NF-κB and IL-1β, accompanied by an increase in the antioxidants NQO1 and HO-1 levels. Similarly, Cand led to the inhibition of the JNK/c-Jun with activation of survivin. In conclusion, Candesartan has mitigated the striatal degeneration and mitochondrial dysfunction induced by 3NP through various mechanistic pathways.

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坎地沙坦对3-硝基丙酸诱导的亨廷顿病的神经保护作用：血管紧张素和CREB/BDNF/PGC1-α信号的调节

肾素-血管紧张素系统与神经退行性疾病如亨廷顿舞蹈症（HD）有关。它由两个轴组成：一个是血管紧张素II型1受体（AT1R）或血管紧张素II型2受体（AT2R），另一个是血管紧张素-(1-7)[Ang-(1-7)]和Mas受体；据报道，后者具有神经保护作用；相反，AT1R的激活与神经退行性疾病有关。本研究旨在通过揭示Ang II/AT2R/Ang-(1-7)/Mas受体、CREB/BDNF/PGC1-α以及JNK/c-Jun轨迹的潜在作用，以及抗凋亡survivin，阐明AT1R阻滞剂坎地沙坦（Candesartan, Cand）在缓解3-硝基丙酸（3NP）诱导的HD引起的神经元变性中的潜在神经保护作用。3NP （10 mg/kg）诱导HD 14 d。大鼠给予坎地沙坦（2.5或5 mg/kg）治疗14 d，分离脑和纹状体进行组织病理学、免疫组织化学和生化分析。GFAP纹状体组织病理学和免疫组织化学检查证实，3NP对大鼠的行为学测试有明显改善，记忆、运动和认知功能增强。此外，Cand激活了Ang II/AT2R/Ang-(1-7)/Mas受体轴。此外，c和刺激纹状体神经营养蛋白CREB/BDNF/PGC1-α的产生，从而降低炎症介质NF-κB和IL-1β的水平，同时增加抗氧化剂NQO1和HO-1的水平。同样，Cand通过激活survivin导致JNK/c-Jun的抑制。总之，坎地沙坦通过多种机制途径减轻了3NP诱导的纹状体变性和线粒体功能障碍。

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来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]