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While the blood\u2013brain barrier (BBB) offers significant protection, this review confronts a central \u201cSafety Paradox\u201d: how can a drug class with a demonstrated high therapeutic index in conventional safety studies be associated with a significant and persistent number of real\u2010world neurological adverse events? We propose that centripetal (retrograde) axonal transport represents a critical, underappreciated pathway for these compounds to access the central nervous system (CNS) from peripheral nerve terminals, offering a mechanistic solution to this paradox. This mechanism, well documented for various toxins and pathogens, could allow antiparasitics to bypass the BBB, leading to direct neuronal effects and contributing to clinical signs such as tremors. We review the neurotoxic mechanisms of these common antiparasitics, the established principles of retrograde axonal transport, and the chemical properties that make them candidates for such transport. Furthermore, we introduce the expanded hypothesis that per\u2010 and polyfluoroalkyl substances (PFASs)\u2014present not only as \u201cinert\u201d ingredients or contaminants but, as recent regulatory findings reveal, also as active ingredients themselves\u2014could act as both facilitators of transport for other neurotoxicants and as direct, cotransported neurotoxic agents. This review synthesizes existing and recent evidence to build a compelling case for axonal transport as a significant contributor to antiparasitic neurotoxicity, discusses its potential for differential clinical impact in young and old dogs, and highlights the urgent need for research into this pathway and the complex toxicological role of formulation components like PFAS.<\/jats:p>","DOI":"10.1155\/jt\/1785323","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T10:02:17Z","timestamp":1775037737000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Centripetal Axonal Transport as a Gateway to the CNS for Veterinary Antiparasitics: Bypassing the Blood\u2013Brain Barrier, Clinical Impact in Vulnerable Age Groups, and the Potential Facilitating Role of PFAS"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7355-8791","authenticated-orcid":false,"given":"Domenico","family":"Britti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romano","family":"Marabelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-069X","authenticated-orcid":false,"given":"Luigino","family":"Calzetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"e_1_2_13_1_2","volume-title":"Veterinary Toxicology: Basic and Clinical Principles","author":"Gupta R. 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