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Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.

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Title: Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.
Authors: Verrillo, Lucia (AUTHOR), Iannotti, Fabio Arturo (AUTHOR), Drongitis, Denise (AUTHOR), Martinello, Katiuscia (AUTHOR), Poeta, Loredana (AUTHOR), Barra, Adriano (AUTHOR), Terrone, Gaetano (AUTHOR), Fucile, Sergio (AUTHOR), Di Marzo, Vincenzo (AUTHOR), Miano, Maria Giuseppina (AUTHOR)
Source: Epilepsia (Series 4). Oct2025, Vol. 66 Issue 10, p4035-4052. 18p.
Subjects: Cannabidiol, Epilepsy, Childhood epilepsy, Seizures (Medicine), Gene expression, Treatment effectiveness, Laboratory mice, Neuroinflammation
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. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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DbLabel: Psychology and Behavioral Sciences Collection
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PubTypeId: academicJournal
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.
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  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Verrillo%2C+Lucia%22">Verrillo, Lucia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Iannotti%2C+Fabio+Arturo%22">Iannotti, Fabio Arturo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Drongitis%2C+Denise%22">Drongitis, Denise</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Martinello%2C+Katiuscia%22">Martinello, Katiuscia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Poeta%2C+Loredana%22">Poeta, Loredana</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Barra%2C+Adriano%22">Barra, Adriano</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Terrone%2C+Gaetano%22">Terrone, Gaetano</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fucile%2C+Sergio%22">Fucile, Sergio</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Di+Marzo%2C+Vincenzo%22">Di Marzo, Vincenzo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Miano%2C+Maria+Giuseppina%22">Miano, Maria Giuseppina</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. Oct2025, Vol. 66 Issue 10, p4035-4052. 18p.
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  Data: <searchLink fieldCode="DE" term="%22Cannabidiol%22">Cannabidiol</searchLink><br /><searchLink fieldCode="DE" term="%22Epilepsy%22">Epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Childhood+epilepsy%22">Childhood epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Seizures+%28Medicine%29%22">Seizures (Medicine)</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression%22">Gene expression</searchLink><br /><searchLink fieldCode="DE" term="%22Treatment+effectiveness%22">Treatment effectiveness</searchLink><br /><searchLink fieldCode="DE" term="%22Laboratory+mice%22">Laboratory mice</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroinflammation%22">Neuroinflammation</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1111/epi.18522
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 18
        StartPage: 4035
    Subjects:
      – SubjectFull: Cannabidiol
        Type: general
      – SubjectFull: Epilepsy
        Type: general
      – SubjectFull: Childhood epilepsy
        Type: general
      – SubjectFull: Seizures (Medicine)
        Type: general
      – SubjectFull: Gene expression
        Type: general
      – SubjectFull: Treatment effectiveness
        Type: general
      – SubjectFull: Laboratory mice
        Type: general
      – SubjectFull: Neuroinflammation
        Type: general
    Titles:
      – TitleFull: Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.
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            NameFull: Verrillo, Lucia
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            – D: 01
              M: 10
              Text: Oct2025
              Type: published
              Y: 2025
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              Value: 66
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              Value: 10
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