In vivo biomarkers of <scp>GABA</scp>ergic function in epileptic rats treated with the <scp>GAT</scp>‐1 inhibitor <scp>E2730</scp>
Bibliographic record
Abstract
Abstract Objective E2730, an uncompetitive γ‐aminobutyric acid (GABA) transporter‐1 (GAT‐1) inhibitor, has potent anti‐seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function. Methods We conducted a randomized cross‐over study, incorporating 1‐week treatments with E2730 (100 mg/kg/day subcutaneous infusion) or vehicle in epileptic post‐KASE rats. KASE rats underwent serial 9.4 T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [ 18 F]Flumazenil positron emission tomography (PET) quantifying GABA A receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)–mediated motor activity, as well as continuous video‐EEG recording to measure spontaneous seizures during each treatment. Age‐matched, healthy control animals treated with E2730 or vehicle were also studied. Results E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure‐free. MRS revealed that E2730‐treated animals had significantly reduced taurine levels. [ 18 F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS. Significance This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".