Yijian Yang, Yaxin Sun, Qian Ouyang, Junqiang Wang, Peng Long, Kaiyue Wang, Yexin Yuan, Yifeng Chen, Zhikun Liu, Jun Huang, Zhiping Zhang, Zhangjie Su, Jian He, Gelei Xiao
Dapagliflozin mitigates PHH by activating the MEK/ERK pathway to enhance autophagy. This mechanistic axis is essential for maintaining NVU integrity, improving glymphatic permeability, and increasing CBF perfusion, presenting SGLT2 inhibition as a promising translational therapy for ICH complications.
BACKGROUND: To investigate the neurovascular protective effects and underlying mechanisms of the SGLT2 inhibitor dapagliflozin on post-hemorrhagic hydrocephalus (PHH) following intracerebral hemorrhage (ICH).
METHODS: An ICH-induced PHH rat model was established. Rats were treated with varying doses of dapagliflozin to evaluate dose-response neuroprotection. To elucidate the underlying molecular pathways, selective autophagy and MEK inhibitors were subsequently administered.
RESULTS: Dapagliflozin dose-dependently attenuated ventricular enlargement, improved neurological deficits, and reduced neuroinflammation post-ICH. Crucially, autophagy inhibition reversed these benefits, concurrently impairing glymphatic clearance, reducing cerebral blood flow (CBF), and disrupting neurovascular unit (NVU) integrity. Furthermore, MEK inhibition counteracted the dapagliflozin-induced enhancement of autophagy, confirming the MEK/ERK pathway's regulatory role.
CONCLUSION: Dapagliflozin mitigates PHH by activating the MEK/ERK pathway to enhance autophagy. This mechanistic axis is essential for maintaining NVU integrity, improving glymphatic permeability, and increasing CBF perfusion, presenting SGLT2 inhibition as a promising translational therapy for ICH complications.