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Therefore, we propose that posttreatment with the PAR\u20101 inhibitor SCH79797 may alleviate symptoms in a 3\u2010nitropropionic acid (3\u2010NP) HD model. Wistar rats were administered 3\u2010NP alone or treated with SCH79797. In silico study showed better blood\u2013brain barrier (BBB) diffusion by SCH79797 than by vorapaxar. Docking showed that SCH79797 blocks thrombin\/PAR\u20101 binding and directly inhibits metalloproteinase (MMP)\u20101. Molecular dynamics confirmed minimal energy deviation and stable interactions with both PAR\u20101 and MMP\u20101 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\u20101, and the expression of PAR\u20101, <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (NMDA) receptor subunits (1 and 2B), and MMP\u20109, while increasing that of claudin\u20105, contributing to BBB integrity. SCH79797 also lowered tumor necrosis factor (TNF)\u2010\u03b1 and mitofusin (Mfn)\u20102, rebalanced the redox system by reducing malondialdehyde (MDA) and enhancing superoxide dismutase (SOD), and prevented 3\u2010NP\u2010induced mitophagy via the PTEN\u2010induced kinase (PINK)\u20101\/ubiquitin pathway. SCH79797 inhibited apoptosis, by reducing caspase\u20103 and cytochrome C, and increased voltage\u2010dependent anion channel\u20101 (VDAC1) to maintain mitochondrial function. Overall, SCH79797 inhibited PAR\u20101 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.<\/jats:p>","DOI":"10.1002\/ardp.202400846","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T18:05:05Z","timestamp":1742839505000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dual inhibition of canonical and noncanonical PAR\u20101 by SCH79797 mitigates neurodegeneration in 3\u2010NP\u2010induced Huntington's disease: An in vivo and in silico approach"],"prefix":"10.1002","volume":"358","author":[{"given":"Raghda T.","family":"Abdel\u2010Latif","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Biochemistry, Faculty of Pharmacy Future University in Egypt Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan S.","family":"El\u2010Abhar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5876-5530","authenticated-orcid":false,"given":"Dalaal M.","family":"Abdallah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9246-2875","authenticated-orcid":false,"given":"Iten M.","family":"Fawzy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Future University in Egypt Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9235-7351","authenticated-orcid":false,"given":"Suzan M.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Biochemistry, Faculty of Pharmacy Future University in Egypt Cairo Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"issue":"10","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nrd.2018.133","volume":"17","author":"Caron N. 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