Resolvin D1 combined with exercise rehabilitation alleviates neurological injury in mice with intracranial hemorrhage via the BDNF/TrkB/PI3K/AKT pathway

Resolvin D1 (RvD1) is an endogenous anti-inflammatory mediator that modulates the inflammatory response and promotes inflammation resolution. RvD1 has demonstrated neuroprotective effects in various central nervous system contexts; however, its role in the pathophysiological processes of intracerebral hemorrhage (ICH) and the potential protective mechanisms when combined with exercise rehabilitation remain unclear. A mouse model of ICH was established using collagenase, and treatment with RvD1 combined with three weeks of exercise rehabilitation significantly improved neurological deficits, muscle strength, learning, and memory in ICH mice while reducing anxiety-like behavior. RvD1 combined with exercise rehabilitation upregulated anti-inflammatory factors, inhibited the inflammatory state, and activated the BDNF/TrkB/PI3K/AKT pathway. TUNEL staining confirmed a decrease in residual apoptotic neurons, while transmission electron microscopy showed an increase in mitochondrial autophagosomes with combined treatment. Mendelian randomization and molecular docking further confirmed the association of RvD1 with targets related to mitophagy and inflammatory factors, clarifying the mechanism of RvD1 involvement. In summary, RvD1 combined with exercise rehabilitation activates the BDNF/TrkB/PI3K/AKT signaling pathway, effectively reduces neuronal apoptosis and inflammatory responses following ICH in mice, and participates in mitochondrial autophagy-related states. This comprehensive therapeutic strategy promotes neurological recovery and provides insights for clinical management of this condition.