Levetiracetam inhibits the Na+ HCO3− transporter Ncbe/NBCn2 (Slc4a10) in the choroid plexus of mice

Abstract

Aim

The Na⁺-dependent Cl⁻/HCO₃⁻ exchanger Ncbe/NBCn2 (Slc4a10) constitutes a major basolateral HCO₃⁻ uptake pathway in the choroid plexus and contributes to cerebrospinal fluid secretion and pH regulation. This study examined whether levetiracetam inhibits Ncbe/NBCn2-mediated transport and alters cerebrospinal fluid acid–base balance, transporter abundance, and cerebrospinal fluid secretion.

Methods

The Ncbe and NBCn1 activity was assessed in heterologous expression systems as Na⁺-dependent pH recovery after intracellular acidification. Na⁺-dependent pH recovery was also measured in isolated mouse choroid plexus epithelial cells. Cerebrospinal fluid pH and apparent secretion rate were assessed in vivo after levetiracetam treatment. Acetazolamide was included as a pharmacological control for inhibition of HCO₃⁻-dependent secretion. Transporter abundance was assessed by immunoblotting, and molecular docking was used to explore interactions between levetiracetam, Ncbe and related SLC4A transporters.

Results

Levetiracetam inhibited Ncbe-mediated transport, whereas no levetiracetam-sensitive NBCn1-mediated component was detected under the same experimental conditions. In choroid plexus epithelial cells, levetiracetam reduced Na⁺-dependent pH recovery to a similar extent as pharmacological inhibition of stilbene-sensitive transport. After 5 days of treatment, levetiracetam was associated with lower cerebrospinal fluid pH and a higher apparent cerebrospinal fluid secretion rate compared with control mice. Levetiracetam reduced Ncbe and NBCe2 abundance, while aquaporin-1 abundance increased. Molecular docking predicted levetiracetam interactions with residues involved in Na⁺ and HCO₃⁻ coordination.

Conclusion

These findings identify Ncbe as a levetiracetam-sensitive HCO₃⁻ transporter in the choroid plexus and support effects on cerebrospinal fluid acid–base balance and secretion.