Modulatory Role of Arbutin on Hepatic Inflammation and Apoptosis After Mild Repetitive Traumatic Brain Injury in Experimental Rats: Involvement of NGF/TrkA and IL-6/JAK2/STAT3 Immune Signaling Crosstalk.

Repetitive traumatic brain injury (RTBI) can cause long-term complications, including persistent neuroinflammation, which can extend beyond the central nervous system, impacting various peripheral organs as liver. This study aimed to explore the neuroprotective and hepatoprotective effects of arbutin treatment in a rat model of mild RTBI (mRTBI), focusing on nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) signaling pathway along with the crosstalk between brain injury and hepatic dysfunction. Animals were randomly assigned into three groups: one served as a normal control (NC) group, while the other two groups were exposed to one blow for 5 days and either left for one week after the fifth blow (mRTBI) or received arbutin intraperitoneally (100 mg/kg/day for 7 days, mRTBI + ARB). Biochemical and histopathological changes were monitored in the brain cortex and the liver. This study revealed that arbutin treatment offered neuroprotection and preserved most of the neuronal structures. Arbutin demonstrated a significant increase in the cortical NGF and TrkA contents, along with a marked upregulation in cortical phosphoinositol-3 kinase (PI3K) and protein kinase B (AKt) mRNA levels compared to the mRTBI group. Furthermore, arbutin decreased cortical and serum inflammatory markers, reflecting its anti-inflammatory power. Peripherally, arbutin treatment resulted in a substantial decrease in hepatic inflammatory markers, Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and caspase-3. These effects preserved hepatocellular histoarchitecture and reduced liver injury markers. Collectively, arbutin effectively modulated the NGF/TrkA signaling pathway, diminished inflammation, and alleviated the detrimental effects of mRTBI on both the brain and liver.