Neuronal nitric oxide synthase activation by tadalafil protects neurological impairments in a zebrafish larva model of hyperammonemia

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-01-15 DOI:10.1016/j.lfs.2024.123325

Poonam Dhiman, Rajneesh Kumar, Damanpreet Singh

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引用次数: 0

Abstract

Aims

Hyperammonaemia (HA) is a metabolic disorder characterized by increased ammonia levels in the blood and is associated with severe neurological impairments. Some previous findings have shown the involvement of the nitric oxide pathway in HA-induced neurological impairments. The current study explored the impact of tadalafil on neurological impairments induced by HA in a zebrafish larval model due to its reported indirect interactions with the nitric oxide pathway.

Material and methods

HA was induced in zebrafish larvae by ammonium acetate exposure from 2 to 9 days post fertilization (dpf). Locomotor and cognitive functions were analysed following the treatment. The levels of gamma-aminobutyric acid (GABA), glutamate, and dopamine were measured in the larval head. The expression of genes associated with apoptosis (baxa and bcl2a), selected neurotransmitter receptors and bdnf was analysed. The protein levels of CREB and nNOS were also quantified.

Key findings

Tadalafil incubation reversed the HA-associated locomotor and cognitive impairments in larvae. The treatment modulated GABA, dopamine, and glutamate levels. An upregulation in the expression of grin1a, gria2b, drd1b, drd2b, bdnf, and bcl2a, and downregulation of gabrz, gabrd, gabrg2 and baxa was observed following tadalafil treatment. The protein expression showed increased nNOS, p-CREB(Ser¹³³), and decreased p-nNOS(Ser⁸⁴⁷) levels in the larvae incubated with tadalafil.

Significance

The study concluded that tadalafil mitigates HA-induced neurological impairments by activating neuronal nitric oxide synthase. The study highlighted the possible application of tadalafil in the symptomatic management of neurological impairments in HA provided its efficacy and safety are further ensured in higher mammals.

Abstract Image

查看原文本刊更多论文

他达拉非激活神经元一氧化氮合酶可保护高氨血症斑马鱼幼鱼模型的神经损伤。

目的：高氨血症（HA）是一种以血液中氨水平升高为特征的代谢性疾病，与严重的神经损伤有关。一些先前的研究结果表明一氧化氮途径参与ha诱导的神经损伤。目前的研究探讨了他达拉非对斑马鱼幼鱼模型中HA诱导的神经损伤的影响，因为它与一氧化氮途径有间接的相互作用。材料与方法：斑马鱼受精后2 ~ 9 d （dpf）乙酸铵暴露诱导HA。治疗后分析运动和认知功能。测定幼虫头部γ -氨基丁酸（GABA）、谷氨酸和多巴胺的水平。分析细胞凋亡相关基因（baxa和bcl2a）、选定神经递质受体和bdnf的表达。同时定量测定CREB和nNOS蛋白水平。主要发现：他达拉非可逆转ha相关的幼虫运动和认知障碍。治疗降低了GABA、多巴胺和谷氨酸水平。他达拉非治疗后，grin1a、gria2b、drd1b、drd2b、bdnf和bcl2a的表达上调，gabrz、gabard、gabrg2和baxa的表达下调。他达拉非处理后，nNOS、p-CREB（Ser133）水平升高，p-nNOS（Ser847）水平降低。意义：本研究认为他达拉非可通过激活神经元一氧化氮合酶减轻ha诱导的神经损伤。该研究强调，如果他达拉非在高等哺乳动物中的有效性和安全性得到进一步保证，他达拉非可能应用于HA患者神经损伤的症状管理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.