Nimodipine and enoxaparin improve neurological outcomes and reduce cerebral edema by modulating glymphatic perivascular spaces in a rabbit model of subarachnoid hemorrhage

BACKGROUND: Glymphatic system dysfunction is a mechanism potentially linked to secondary brain injury after subarachnoid hemorrhage (SAH). While nimodipine and enoxaparin are commonly used in clinical practice, their influence on perivascular clearance mechanisms remains unexplored. This exploratory study aimed to provide preliminary insights into how these agents might modulate the glymphatic pathway and influence early functional recovery in an experimental SAH model, addressing a gap in understanding the mechanistic effects of these standard treatments. METHODS: Twenty male New Zealand white rabbits (n = 5/group) were randomized into Control, SAH+Vehicle, SAH+Nimodipine (0.05 mg/kg), and SAH+Enoxaparin (1 mg/kg) groups. SAH was induced via a modified two-hemorrhage cisterna magna injection model. Treatments were administered intraperitoneally starting 2 h post-SAH for five days. Neurological function and food intake were assessed using validated scales (Endo Food Intake and Neurologic Function Scale). Post-mortem, brain edema (wet/dry weight), perivascular space expansion (histopathology), and Aquaporin-4 (Aqp-4) gene expression (RT-qPCR) were quantified. RESULTS: Both nimodipine and enoxaparin were associated with improved neurological (p = 0.002, p = 0.012) and food intake scores (p = 0.004, p = 0.009) versus SAH+Vehicle. Enoxaparin showed a more pronounced reduction in brain edema (p < 0.01 vs. SAH and nimodipine). Histologically, both treatments reduced the perivascular-to-vascular area ratio (p < 0.05), potentially reflecting attenuated perivascular fluid accumulation. No statistically significant changes in Aqp-4 gene expression were observed (p = 0.875). CONCLUSION: These preliminary findings suggest that nimodipine and enoxaparin may influence perivascular clearance, potentially contributing to improved functional outcomes. While offering an exploratory link between standard treatments and perivascular spaces, further mechanistic studies are required to confirm these pathways and their clinical relevance.