Dhiman Poonam, Kumar Rajneesh, Singh Damanpreet
Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Life Sci. 2025 Jan 15;361:123325. doi: 10.1016/j.lfs.2024.123325. Epub 2024 Dec 20.
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.
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.
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(Ser), and decreased p-nNOS(Ser) levels in the larvae incubated with tadalafil.
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.
高氨血症（HA）是一种代谢紊乱疾病，其特征为血液中氨水平升高，并与严重的神经功能障碍相关。先前的一些研究结果表明一氧化氮途径参与了HA诱导的神经功能障碍。由于据报道他达拉非与一氧化氮途径存在间接相互作用，本研究在斑马鱼幼体模型中探讨了他达拉非对HA诱导的神经功能障碍的影响。
在受精后2至9天（dpf），通过暴露于醋酸铵在斑马鱼幼体中诱导产生HA。处理后分析运动和认知功能。测量幼体头部中γ-氨基丁酸（GABA）、谷氨酸和多巴胺的水平。分析与细胞凋亡相关的基因（baxa和bcl2a）、选定的神经递质受体和脑源性神经营养因子（BDNF）的表达。还对CREB和nNOS的蛋白水平进行了定量。
他达拉非孵育可逆转幼体中与HA相关的运动和认知障碍。该处理调节了GABA、多巴胺和谷氨酸水平。他达拉非处理后观察到grin1a、gria2b、drd1b、drd2b、BDNF和bcl2a的表达上调，以及gabrz、gabrd、gabrg2和baxa的表达下调。蛋白表达显示，在与他达拉非孵育的幼体中，nNOS、p-CREB（Ser）水平升高，而p-nNOS（Ser）水平降低。
该研究得出结论，他达拉非通过激活神经元型一氧化氮合酶减轻HA诱导的神经功能障碍。该研究强调了他达拉非在HA神经功能障碍症状管理中的可能应用，前提是在高等哺乳动物中进一步确保其疗效和安全性。
