PUBLICATION

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

Authors
Dhiman, P., Kumar, R., Singh, D.
ID
ZDB-PUB-250109-19
Date
2025
Source
Life sciences   361: 123325123325 (Journal)
Registered Authors
Singh, Damanpreet
Keywords
Brain-derived neurotrophic factor, Cognitive impairments, Locomotor deficits, Neurotransmitters, PDE-5 inhibitor, Partition preference
MeSH Terms
  • Disease Models, Animal*
  • Animals
  • Larva*/drug effects
  • Tadalafil*/pharmacology
  • Tadalafil*/therapeutic use
  • Locomotion/drug effects
  • Zebrafish*
  • Nitric Oxide Synthase Type I*/genetics
  • Nitric Oxide Synthase Type I*/metabolism
  • Neuroprotective Agents/pharmacology
  • Hyperammonemia*/drug therapy
  • Hyperammonemia*/metabolism
  • Nervous System Diseases/drug therapy
  • Nervous System Diseases/etiology
  • Nervous System Diseases/metabolism
PubMed
39710060 Full text @ Life Sci.
Citation
Dhiman, P., Kumar, R., Singh, D. (2025) Neuronal nitric oxide synthase activation by tadalafil protects neurological impairments in a zebrafish larva model of hyperammonemia. Life sciences. 361:123325123325.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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