Pharmacological evaluation of Orai-1 inhibitor in 3-nitropropionic acid-induced Huntington disease.

Abstract

OBJECTIVES: Huntington's disease (HD) is a neurodegenerative condition characterized by a gradual decline in motor skills, cognitive function, and mental health. The 3-nitropropionic acid (3-NPA) model simulates HD-like pathology, which involves calcium dysregulation. To establish a structural basis for targeting Orai-1, in-silico docking was conducted prior to assessing the neuroprotective effects of the Orai-1 inhibitor Synta-66 in a 3-NPA-induced HD model. METHODS: Mice were randomly divided into five groups (n = 8): normal control, 3-NPA (10 mg/kg, i.p.), 3-NPA combined with tetrabenazine (3 mg/kg, i.p.), 3-NPA combined with Synta-66 (5 mg/kg, i.p.), and 3-NPA combined with Synta-66 (10 mg/kg, i.p.). In-silico docking was used to evaluate the interactions of Synta-66 with Orai-1 and other targets related to neurodegeneration. Various parameters including behavioural, biochemical, oxidative stress, and neuroinflammatory markers were assessed. Additionally, the ELISA expression of Orai-1 protein and Ca2+ levels were measured. KEY FINDINGS: In-silico analysis revealed that Synta-66 binds effectively with Orai-1 and its related targets. In vivo studies showed that 3-NPA caused notable motor impairments, biochemical changes, neuroinflammation, and disruptions in Ca2+ regulation. Administration of Synta-66 led to a dose-dependent recovery of body weight, enhancement of behavioural performance, normalization of biochemical and neuroinflammatory indicators, and a decrease in Orai-1 protein levels and intracellular Ca2+ concentrations, similar to the effects of tetrabenazine. CONCLUSION: The findings suggest the therapeutic potential of targeting Orai-1 channel using the inhibitor Synta-66 could serve as a neuroprotective treatment in a 3-NPA-induced HD model in mice.