Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation.

Perioperative neurocognitive disorder (PND) is a concern following anesthesia, particularly in individuals at risk for Alzheimer’s disease (AD). This study compared the cognitive and pathological effects of propofol and remimazolam in a mouse model with AD following surgery. Five-month-old male ApoE4-KI mice underwent abdominal surgery under either propofol (170 mg/kg) or remimazolam (85 mg/kg) anesthesia. Cognitive function was assessed using the Morris water maze and Y-maze, and neuronal apoptosis and amyloid-beta (Aβ) deposition in the CA3 and dentate gyrus (DG) of the hippocampus were evaluated preoperatively and at 2, 4, and 7 days postoperatively. Both groups showed similar postoperative cognitive functions, with increased relative escape latency at day 2 and decreased relative spontaneous alternation at days 4 and 7. However, the neuropathological analysis revealed that propofol-induced significantly more neuronal death in the CA3 (days 4 and 7) and DG (days 2, 4, and 7), and greater Aβ accumulation in the CA3 (days 2 and 4) and DG (days 2 and 7) compared to remimazolam (p < 0.05). Propofol was associated with more pronounced neuropathologic changes in the hippocampus compared to remimazolam. These findings suggest remimazolam may be a safer anesthetic for patients at risk for neurodegenerative disorders, as it is associated with less severe hippocampal pathology, which is characteristic of AD.

The gut–brain axis regulates brain functions and maintains central nervous system homeostasis and intestinal balance. Migraine patients often present with gastrointestinal (GI) comorbidities, with stronger associations observed in chronic migraine (CM) than in episodic migraine (EM). To investigate migraine-related GI alterations, nitroglycerin (NTG)-induced mouse models of EM (N = 15) and CM (N = 15) were established using single or repeated NTG injections (10 mg/kg). EM mice were euthanized 4 h after a single injection, whereas CM mice received NTG every other day for 9 days and were euthanized after the fifth injection. On the day of sacrifice, GI tissues were analyzed for morphological changes, cytokine expression, calcitonin gene-related peptide (CGRP) levels, and immune cell profiles. NTG-treated groups exhibited significant reductions in both food intake and body weight compared with controls. In addition, colon length was markedly shortened in the chronic migraine (CM) model (p < 0.01). Molecular analyses revealed distinct cytokine expression profiles between models: the episodic migraine (EM) model showed increased levels of proinflammatory cytokines (IL-1β, IL-6, and IL-8; p < 0.01), whereas the CM model displayed elevated anti-inflammatory cytokines (IL-4, IL-10, and TGF-β; p < 0.01), particularly in the colon. CGRP expression was also markedly upregulated throughout the gastrointestinal tract, with the highest expression observed in the colon of CM mice (p < 0.01). Flow cytometric immune profiling further demonstrated divergent immune cell patterns, with increased Th17 (p = 0.0085) and B cell (p = 0.0199) populations in EM, while CM was characterized by enrichment of T cells (p = 0.0221), regulatory T cells (Tregs) (p = 0.0114), and macrophages (p = 0.0062), indicating more pronounced immune alterations in the distal colon. These findings indicate that CM involves more severe gut–brain axis dysregulation than EM, supporting the potential of gut-targeted therapies as adjunct strategies in chronic migraine.