Dual inhibition of canonical and noncanonical PAR-1 by SCH79797 mitigates neurodegeneration in 3-NP-induced Huntington's disease: An in vivo and in silico approach

Abstract

Though abnormal platelet function is detected in Huntington's disease (HD), thrombin's role is indistinct. Through protease-activated receptor 1 (PAR-1) activation, thrombin triggers intricate pathways relevant to HD. Therefore, we propose that posttreatment with the PAR-1 inhibitor SCH79797 may alleviate symptoms in a 3-nitropropionic acid (3-NP) HD model. Wistar rats were administered 3-NP alone or treated with SCH79797. In silico study showed better blood–brain barrier (BBB) diffusion by SCH79797 than by vorapaxar. Docking showed that SCH79797 blocks thrombin/PAR-1 binding and directly inhibits metalloproteinase (MMP)-1. Molecular dynamics confirmed minimal energy deviation and stable interactions with both PAR-1 and MMP-1 and root mean square deviation (RMSD) verified conformational stability. In the in vivo part, behavioral and striatal improvements were observed, with SCH79797 reducing striatal levels of thrombin and MMP-1, and the expression of PAR-1, N-methyl-d-aspartate (NMDA) receptor subunits (1 and 2B), and MMP-9, while increasing that of claudin-5, contributing to BBB integrity. SCH79797 also lowered tumor necrosis factor (TNF)-α and mitofusin (Mfn)-2, rebalanced the redox system by reducing malondialdehyde (MDA) and enhancing superoxide dismutase (SOD), and prevented 3-NP-induced mitophagy via the PTEN-induced kinase (PINK)-1/ubiquitin pathway. SCH79797 inhibited apoptosis, by reducing caspase-3 and cytochrome C, and increased voltage-dependent anion channel-1 (VDAC1) to maintain mitochondrial function. Overall, SCH79797 inhibited PAR-1 canonically and noncanonically to counter excitotoxicity, oxidative stress, inflammation, apoptosis, and mitophagy, thereby preserving BBB and mitochondrial integrity, improving histological outcomes, and enhancing behavioral performance.