MMP-9 inhibition alleviates postoperative cognitive dysfunction by improving glymphatic function via regulating AQP4 polarity
- Int Immunopharmacol. 2023 Nov 23:126:111215. doi: 10.1016/j.intimp.2023.111215.
- 1. The First Affiliated Hospital of Ningbo University, Ningbo 315000, China; Health Science Center, Ningbo University, Ningbo 315000, China.
- 2. The First Affiliated Hospital of Ningbo University, Ningbo 315000, China.
- 3. Health Science Center, Ningbo University, Ningbo 315000, China.
- 4. The First Affiliated Hospital of Ningbo University, Ningbo 315000, China; Health Science Center, Ningbo University, Ningbo 315000, China. Electronic address: [email protected].
Postoperative cognitive dysfunction (POCD) is a common complication after surgery, characterized by deficits in memory, attention and cognitive flexibility. However, the underlying mechanisms of POCD remain unclear. Neuroinflammation and blood-brain barrier disruption have been implicated as potential pathological processes. This study explores the neuroprotective effects and mechanisms of the matrix metalloproteinase（MMP-9）inhibitor GM6001 against POCD. We hypothesize GM6001 may reduce neuroinflammation and preserve blood-brain barrier integrity through direct inhibition of MMP-9. Moreover, GM6001 may stabilize aquaporin-4 polarity and glymphatic clearance function by modulating MMP-9-mediated cleavage of dystroglycan, a key protein for aquaporin-4 anchoring. Our results demonstrate GM6001 alleviates postoperative cognitive deficits and neuroinflammation. GM6001 also preserves blood-brain barrier integrity and rescues aquaporin-4 mislocalization after surgery. This study reveals a novel dual role for MMP-9 inhibition in cognitive protection through direct anti-neuroinflammatory effects and regulating aquaporin-4 membrane distribution. Targeting MMP-9 may represent a promising strategy to prevent postoperative cognitive dysfunction by integrating multiple protective mechanisms.