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.