Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1
Bibliographic record
Abstract
Abstract Objective Developmental and epileptic encephalopathy type 1 (DEE1) is a rare drug‐resistant pediatric epilepsy caused by trinucleotide repeat expansions in the X‐linked ARX gene, leading to elongation of the first polyalanine tract. It presents with early onset tonic seizures or spasms, developmental and cognition delay, and high risk of premature mortality. We evaluated the therapeutic potential of highly purified cannabidiol (CBD) in Arx (GCG)7/Y mice, a genetic DEE1 model that replicates key features of the human condition. Methods Arx (GCG)7/Y mice received daily intraperitoneal CBD (100 mg/kg) for 7 days. The epileptic phenotype was evaluated via video monitoring and a scoring matrix. In Arx ‐DEE1 male cortex, real‐time polymerase chain reaction and Western blotting assessed CBD effects on proinflammatory and neuronal markers. Microglial morphology was analyzed by Iba1 immunostaining and Sholl analysis. In vitro patch‐clamp recordings tested CBD activity on Arx (GCG)7/Y cortical neurons. Results CBD reduced the severity and frequency of spontaneous recurrent seizures and significantly extended the lifespan of epileptic mice. In mutant symptomatic mice, CBD activated peroxisome Pparg expression and the concurrent desensitization/inactivation of TRPV1 channels. Additionally, CBD counteracted the dysregulated expression of the proinflammatory genes Ptgs2, Mmp9, Il12, Cd68, Ccl2, and Irf3, while also restoring normal microglial morphology. Further molecular analysis demonstrated that CBD effectively offsets normal alternative splicing for the presynaptic receptor genes Nrnx1 and Nrnx3 . Consistent with this, CBD rescued proper Nrnx1 splicing in mutant cortical neurons after K + ‐induced depolarization. Finally, we found that CBD reduced neuronal excitability by inducing hyperpolarization, raising the action potential threshold, and reducing the frequency and mean charge of inhibitory postsynaptic currents and the mean charge of excitatory postsynaptic currents. Significance These findings represent the first preclinical evidence of CBD efficacy in a murine model of genetic DEE1, identifying CBD‐sensitive downstream targets and paving the way to further exploration of CBD effects in this disease for future clinical consideration.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".