Electroacupuncture promotes the efficacy of anti-seizure drugs in acute seizure models by enhancing the permeability of the blood-brain barrier

The blood-brain barrier (BBB) restricts the effective penetration of anti-seizure drugs (ASDs) into the brain, resulting in unwanted peripheral side effects of ASDs at therapeutic doses. Electroacupuncture (EA) has shown good efficiency in enhancing the drug molecules’ permeability of BBB. We aimed to test the hypothesis that EA could improve the efficacy of ASDs for acute epileptic seizures by increasing their intracerebral concentrations. Firstly, quantitative analysis of electroacupuncture-mediated alterations in blood-brain barrier permeability was performed involved two metrics: (1) Evans Blue penetration measured by the in vivo imaging system (IVIS) fluorescence imaging, and (2) brain tissue drug levels analyzed with high-performance liquid chromatography-mass spectrometry (HPLC) following intraperitoneal injection of ASDs, both experiments were performed after EA and intraperitoneal injection. Next, assessment of anti-seizure efficacy in models, as follow: post-electroacupuncture stimulation at GV20 and GV16, therapeutic and sub-doses of ASDs were delivered via intraperitoneal injection. Seizure susceptibility was evaluated using two distinct provocation methods: the classic maximal electroshock tests and the pentylenetetrazol ( i.p. ) treatments, with seizure intensity being record. Lastly, the safety profile of electroacupuncture was preliminarily evaluated through open field test (OFT) and hot plate experiments. We initially confirmed that EA was capable of enhancing the permeability of the BBB and increasing the intra-cerebral concentration of valproate acid. Then, behavioral experiments confirmed that EA combined with ASD exhibited superior efficacy compared to ASD monotherapy for acute seizures in both models. This enhancing efficacy could be extended to different ASDs with distinct acting mechanisms, including valproate acid, lamotrigine, lacosamide, and levetiracetam. And the electroacupuncture stimulation parameters were confirmed to be safe in mice through comprehensive behavioral evaluation. The results of the present study indicated that EA could improve the therapeutic efficacy of ASDs by enhancing the concentration of drugs in the brain, and provided a blueprint for better anti-seizure management with potential translational significance.