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Published on: June 22, 2022
SGLT2 inhibitor alleviates hydrocephalus post intracerebral hemorrhage through enhancing autophagy via activating
Yijian Yang1, Yaxin Sun1, Qian Ouyang2
1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Diagnosis and Treatment Center for Hydrocephalus, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
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.
