Modulation of adenosine signaling reverses 3-nitropropionic acid-induced bradykinesia and memory impairment in adult zebrafish

Huntington's disease (HD) is a neurodegenerative disorder, characterized by motor dysfunction, psychiatric disturbance, and cognitive decline. In the early stage of HD, occurs a decrease in dopamine D-2 receptors and adenosine A(2A )receptors (A(2A)R), while in the late stage also occurs a decrease in dopamine D-1 receptors and adenosine A(1 )receptors (A(1)R). Adenosine exhibits neuromodulatory and neuroprotective effects in the brain and is involved in motor control and memory function. 3-Nitropropionic acid (3-NPA), a toxin derived from plants and fungi, may reproduce HD behavioral phenotypes and biochemical characteristics. This study investigated the effects of acute exposure to CPA (A(1)R agonist), CGS 21680 (A(2A)R agonist), caffeine (non-selective of A(1)R and A(2A)R antagonist), ZM 241385 (A(2A)R antagonist), DPCPX (A(1)R antagonist), dipyridamole (inhibitor of nucleoside transporters) and EHNA (inhibitor of adenosine deaminase) in an HD pharmacological model induced by 3-NPA in adult zebrafish. CPA, CGS 21680, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA were acutely administered via i.p. in zebrafish after 3-NPA (at dose 60 mg/kg) chronic treatment. Caffeine and ZM 241385 reversed the bradykinesia induced by 3-NPA, while CGS 21680 potentiated the bradykinesia caused by 3-NPA. Moreover, CPA, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA reversed the 3-NPA-induced memory impairment. Together, these data support the hypothesis that A(2A)R antagonists have an essential role in modulating locomotor function, whereas the activation of A(1)R and blockade of A(2A)R and A(1)R and modulation of adenosine levels may reduce the memory impairment, which could be a potential pharmacological strategy against late-stage symptoms HD.

Automated summary

This study investigated the effects of acute exposure to different substances in an HD pharmacological model induced by 3-NPA in adult zebrafish. The results showed that some substances could reverse or exacerbate the bradykinesia symptoms of HD, and also reverse memory impairment. The study suggests that these substances play an important role in modulating locomotor function and memory, and may be a potential pharmacological strategy against late-stage symptoms of HD.