Propranolol improves cognitive function and glymphatic system recovery through STAT3/MMP2 pathway after TBI

There is no effective treatment for cognitive impairment after traumatic brain injury (TBI). Previous studies have demonstrated that propranolol may improve cognitive function. The glymphatic system plays a crucial role in cognitive impairment after TBI. Thus, we explored the mechanism by which propranolol improves cognitive function and promotes glymphatic system recovery after TBI. In vivo, rats were subjected to controlled cortical impact (CCI) and treated with saline, propranolol, S31-201 (an inhibitor of STAT3) and SB-3CT (an inhibitor of MMP2) respectively. Rats then underwent a battery of cognitive tests. We also assessed white matter (WM) integrity and glymphatic system function. The expression of phosphorylated tau (p-tau), amyloid-β (Aβ), aquaporin 4 (AQP4), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), and matrix metalloproteinase-2 (MMP2) was evaluated by immunocytochemistry and Western blot. In vitro, the levels of STAT3, p-STAT3, MMP2 and AQP4 were assessed after astrocytes were treated with propranolol, noradrenaline, S31-201 and SB-3CT respectively. In vivo results showed that propranolol, S31-201 and SB-3CT improved cognitive function and restored glymphatic system function after TBI. The deposition of p-tau and Aβ was decreased, and WM integrity was restored in TBI rats treated with propranolol, S31-201 and SB-3CT. Propranolol, S31-201 and SB-3CT induced the overexpression of AQP4 in blood vessels and astrocytes after TBI. In addition, the levels of p-STAT3 and MMP2 were knocked down in propranolol-treated TBI rats. In vitro, propranolol reversed the upregulated expression of p-STAT3 and MMP2 in noradrenaline-treated astrocytes. The noradrenaline-induced impairment of AQP4 expression in astrocytes was antagonized by propranolol, S31-201 and SB-3CT. In conclusion, propranolol may improve cognitive function and facilitate glymphatic system functional recovery after TBI through the STAT3/MMP2 pathway.