Long-Term Exposure to Tire-Derived 6-PPD Quinone Causes Neurotoxicity and Neuroinflammation via Inhibition of HTR2A in C57BL/6 Mice

N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6-PPDQ), a novel contaminant derived from tire wear, has raised concerns due to its potential neurotoxicity, yet its long-term effects on mammalian neurological health remain poorly understood. This study investigates the neurotoxic and neuroinflammatory impacts of prolonged 6-PPDQ exposure using male C57BL/6 mice. Behavioral assessments revealed significant cognitive deficits, while biochemical analyses demonstrated increased levels of reactive oxygen species, apoptosis, and blood–brain barrier (BBB) disruption. Elevated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and activation of microglial cells were observed, indicating a robust neuroinflammatory response. Network pharmacology and molecular docking identified serotonin receptor HTR2A as a key target through which 6-PPDQ mediates its toxic effects. Activation of HTR2A by the agonist DOI (2,5-dimethoxy-4-iodoamphetamine) mitigated these effects, suggesting a potential therapeutic strategy. These findings provide the first evidence of 6-PPDQ-induced neurotoxicity in mammals, underscoring the need for preventive measures to protect neurological health.