Centripetal Axonal Transport as a Gateway to the CNS for Veterinary Antiparasitics: Bypassing the Blood-Brain Barrier, Clinical Impact in Vulnerable Age Groups, and the Potential Facilitating Role of PFAS.

Abstract

The widespread use of veterinary antiparasitics, including neonicotinoids, isoxazolines, avermectins, and pyrethroids, is essential for canine health but raises concerns regarding potential neurotoxicity, particularly in young and geriatric animals. While the blood-brain barrier (BBB) offers significant protection, this review confronts a central "Safety Paradox": 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-world 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- and polyfluoroalkyl substances (PFASs)-present not only as "inert" ingredients or contaminants but, as recent regulatory findings reveal, also as active ingredients themselves-could 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.