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

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(Ser), and decreased p-nNOS(Ser) 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.