Ambroxol alleviates hippocampus injury after BRIR through suppression of the IRE1α/TRAF2 signaling pathway

Acute kidney injury(AKI) is commonly linked to cognitive and neurological impairments. The study aims to investigate the relationship between bilateral renal ischemia reperfusion (BRIR) and hippocampal damage and evaluates the effects of ambroxol against BRIR-induced hippocampal injury and neuroinflammation. Thirty adult male rats were randomly assigned to three groups: control (laparotomy without renal occlusion), BRIR model (bilateral renal ischemia was induced by clamping both renal pedicles for 60 min, followed by 3 days of reperfusion), and ambroxol treatment (70 mg/kg, I.P., once daily during reperfusion). Hippocampal injury was assessed through biochemical (ELISA, Western blot, and PCR), histopathological, and behavioral analysis. Compared to the control group, BRIR significantly increased serum Cr, BUN, and renal injury markers (MDA, MCP-1, KIM-1) (p < 0.0001), along with notable renal tubular degeneration and necrosis. In the hippocampus, BRIR elevated inflammatory markers (NF-κB, TNF-α, MCP-1, IL-1β, G-CSF), reduced antioxidants (SOD, GSH), and altered apoptotic markers (increased Bax, decreased Bcl-2) (all p < 0.0001). Behavioral tests revealed impairments in learning, memory, and locomotor activity. Histology showed degeneration of pyramidal neurons in the CA1 region. Ambroxol treatment significantly ameliorated these effects, preserving CA1 neuronal structure, restoring blood-brain barrier (BBB) integrity (via Occludin and Claudin-5), enhancing BDNF and IBA-1 expression, and modulating MAPK/NF-κB and IRE1α/TRAF2 signaling pathways. Finally, BRIR induces both renal and hippocampal injury. Ambroxol mitigates this damage by reducing oxidative stress and inflammation, repairing BBB components, and regulating endoplasmic reticulum stress pathways (ERS).