SGLT2 inhibitor alleviates hydrocephalus post intracerebral hemorrhage through enhancing autophagy via activating MEK/ERK pathway.

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.