Neuroinflammatory Modulation by Remote Ischemic Conditioning in Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a leading global cause of disability. Repetitive mild TBI (r-mTBI) is associated with persistent neuroinflammation. Remote ischemic conditioning (RIC) is a non-invasive intervention shown to reduce neuroinflammation, key characteristic of r-mTBIs. This study evaluated whether RIC improves neuroinflammation in a pre-clinical model of r-mTBI. Thirty-two male C57BL/6 mice were assigned to four groups: no RIC/sham, RIC/sham, no RIC/r-mTBI, and RIC/r-mTBI. RIC consisted of four cycles of 5-minute ischemia and 5-minute reperfusion applied to the hindlimbs daily for 14 days. Starting the following day, r-mTBI was induced using a lateral impact model, with one mTBI administered daily for 5 days. Neuroinflammation was assessed using immunohistochemistry for astrocytic and microglial markers in the motor cortex and hippocampus. Whole-brain homogenates were used to profile cytokine and chemokine expression. Mice receiving RIC demonstrated a significant reduction in microglial mean fluorescence intensity and cellular density in the motor cortex compared with the no-RIC group. There were significant alterations in IL-1α, IL-2, IP-10, and MIP-2 levels. RIC showed modest beneficial effects on neuroinflammation following r-mTBI. With our prior findings demonstrating improved motor function, these results support RIC’s efficacy for r-mTBI. Future studies will investigate underlying mechanisms using proteomics and transcriptomics.