Validates blood pressure control for seizure management: Jujuboside B exerts antiseizure effects via blood pressure reduction and activation of NTS-VGLUT2neurons.

Abstract

BACKGROUND: The interaction between the cardiovascular and brain is crucial for epileptogenesis, but the underlying mechanisms are unclear. Ziziphi Spinosae Semen (ZSS), a traditional herb used for its heart-nourishing and mind-calming effects, is hypothesized to potentially suppress seizures through modulation of cardiovascular function. PURPOSE: To explore how jujuboside B (JuB) from ZSS affects epilepsy through cardiovascular-brain crosstalk. METHODS: In acute seizure models, epileptic activity and cardiovascular parameters were evaluated via Electroencephalogram/ Electromyography (EEG/EMG) recording, multiphysiological signal monitoring, laser speckle blood flow imaging, and left vagotomy. Whole-brain c-Fos mapping revealed that nucleus of the solitary tract (NTS) was an activated region. Chemogenetic methods and in vivo multi-channel recording techniques were used to activate neurons expressing vesicular glutamate transporter 2 in NTS (NTS-VGLUT2) neurons and monitor neuronal activity in the dentate gyrus (DG). RESULTS: JuB exerts both hypotensive and antiseizure effects. Sodium nitroprusside (SNP) elicited similar effects, establishing a therapeutic link between blood pressure reduction and seizure suppression. JuB increased vagal nerve discharge, and its antiseizure activity was abolished by left vagotomy. Whole-brain c-Fos mapping identified NTS and DG as key responsive regions. JuB selectively activated NTS-VGLUT2neurons, augmenting their firing. Chemogenetic activation of these neurons inhibited DG neuronal hyperactivity and suppressed pentylenetetrazole (PTZ)-induced seizures. CONCLUSION: JuB exerts its antiseizure effect through the activation of vagal-mediated NTS-VGLUT2neurons and the inhibition of DG neurons. This reconciles cardiovascular and neurological modulation. These findings elucidate JuB's pharmacological basis, advance epileptic pathophysiology understanding, and support personalized therapeutic strategies for epilepsy with hypertension.