Hippocampal myelin damage contributes to cognitive impairment in a rat model of trigeminal neuropathic pain: Neuroprotective and anti-inflammatory effects of atorvastatin

Chronic neuropathic pain is increasingly recognized to impair cognitive function, yet its underlying mechanisms remain unclear. This study tested whether trigeminal neuropathic pain (TNP) modeled by distal infraorbital nerve chronic constriction injury (dION-CCI) provokes hippocampal myelin damage associated with cognitive dysfunction, and whether atorvastatin attenuates mechanical hypersensitivity and cognitive deficits. We also explored whether these effects relate to attenuation of the CD95/CD95L (Fas/Fas ligand)–NF-κB–interleukin-1β (IL-1β) axis and preservation of myelin integrity. Behavioral assessments included facial mechanical withdrawal threshold testing and Morris water maze analysis of spatial learning and memory. Hippocampal myelin integrity was examined using Western blotting of myelin basic protein (MBP), immunofluorescence, transmission electron microscopy, and Luxol Fast Blue staining. TNP rats exhibited significant facial mechanical hypersensitivity and impaired spatial learning, accompanied by decreased MBP expression and myelin disruption. Atorvastatin (10 mg/kg/day) attenuated mechanical hypersensitivity, improved learning ability, preserved myelin structure, and restored MBP levels. Inflammatory markers including CD95, CD95L, NF-κB, and IL-1β were elevated in TNP rats and downregulated by atorvastatin. These findings suggest that hippocampal myelin damage may underlie TNP-related cognitive deficits, and atorvastatin may exert neuroprotective effects by mitigating neuroinflammation and myelin injury. Hippocampal myelin damage links trigeminal neuropathic pain to cognitive decline. Distal infraorbital nerve CCI (dION-CCI) activates CD95/CD95L–NF-κB–IL-1β signaling. Atorvastatin reduces facial mechanical hypersensitivity and improves learning. Atorvastatin preserves hippocampal myelin and dampens neuroinflammation. Hippocampal inflammation and myelin loss underlie TNP-related cognitive deficits.