# Selective Deletion of NBCe1 in Reactive Astrocytes Attenuates Ischemic Stroke Brain Damage

## TL;DR

Deleting a specific transporter in reactive astrocytes reduces brain damage and improves recovery after stroke.

## Contribution

This study demonstrates that targeting NBCe1 in reactive astrocytes can mitigate stroke damage and improve recovery outcomes.

## Key findings

- Deleting NBCe1 in reactive astrocytes reduces infarct volume and brain swelling after stroke.
- Astrocytic NBCe1 deletion preserves AQP4 polarization and reduces blood-brain barrier permeability.
- Targeting NBCe1 in astrocytes leads to improved neurological function and anti-inflammatory effects post-stroke.

## Abstract

The electrogenic sodium bicarbonate transporter 1 (NBCe1/Slc4a4), predominantly expressed in astrocytes, is important for brain pH regulation and homeostasis. Increased NBCe1 expression in reactive astrocytes has been associated with neuronal degeneration in ischemic stroke. However, the effects of astrocytic NBCe1 inhibition in stroke remain contradictory, and the underlying mechanisms are unclear. Here, we show that wild‐type (WT) mice exhibited elevated NBCe1 expression in the peri‐lesional regions at 3 days post‐stroke. Astrocytic Nbce1 gene deletion in inducible Gfap‐Cre
ERT2+/−; Nbce1
f/f mice (Nbce1
iΔAstro) resulted in a significant reduction in NBCe1 mRNA and protein expression in astrocytes. Compared to WT stroke mice, Nbce1
iΔAstro mice displayed reduced infarct volume, decreased brain swelling, improved cerebral blood flow, and accelerated neurological function recovery in the 1–5‐day acute post‐stroke period. Moreover, Nbce1
iΔAstro stroke mice exhibited decreased blood–brain barrier (BBB) permeability, accompanied by preserved perivascular AQP4 polarization, upregulation of Kir4.1 protein expression, and reduced astrocyte domain volume. Importantly, Nbce1
iΔAstro stroke brains revealed an anti‐inflammatory cytokine profiling signature, marked by increased TIMP‐1 expression. Together, our findings suggest that astrocytic upregulation of pH regulatory protein NBCe1 after stroke contributes to increased BBB permeability, reactive astrogliosis, inflammation, and perivascular AQP4 dysregulation. Targeting astrocytic NBCe1 may represent a promising new therapeutic strategy to mitigate astroglial dysfunction in the post‐stroke brain.

NBCe1 is upregulated in reactive astrocytes following ischemic stroke. Deletion of astrocytic Nboe1 reduces stroke volume, preserves AQP4 polarization, reduces BBB permeability, and improves neurological function after ischemic stroke.

NBCe1 is upregulated in reactive astrocytes following ischemic stroke. Deletion of astrocytic Nboe1 reduces stroke volume, preserves AQP4 polarization, reduces BBB permeability, and improves neurological function after ischemic stroke.