Targeting Hsp90 with cemdomespib reduces seizure burden and alters disease course in preclinical epilepsy models.
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| Title: | Targeting Hsp90 with cemdomespib reduces seizure burden and alters disease course in preclinical epilepsy models. |
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| Authors: | Sheeni, Yara (AUTHOR), Singh, Prince Kumar (AUTHOR), Sandouka, Sereen (AUTHOR), Zhang, Taige (AUTHOR), Nemirovski, Alina (AUTHOR), Saadi, Aseel (AUTHOR), Olowe Taiwo, Rhoda (AUTHOR), Walker, Matthew C. (AUTHOR), Shekh‐Ahmad, Tawfeeq (AUTHOR) |
| Source: | Epilepsia (Series 4). Apr2026, Vol. 67 Issue 4, p1665-1678. 14p. |
| Subjects: | Seizures (Medicine), Heat shock proteins, Epilepsy, Neuroinflammation, Mitochondria, Oxidative stress |
| Abstract: | Objective: Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequent cognitive and psychiatric comorbidities. Although current antiseizure medications provide symptomatic relief, they fail to prevent or modify epileptogenesis. Heat shock protein 90 (Hsp90) is increasingly recognized as a regulator of neuroinflammatory and oxidative stress pathways implicated in seizure generation and disease progression. Here, we investigated the therapeutic potential of cemdomespib, a novel and selective Hsp90 inhibitor, across complementary preclinical models of epilepsy. Methods: In vitro, cemdomespib was evaluated in the low‐magnesium model of epileptiform activity for its effects on neuronal calcium dynamics, mitochondrial membrane stability, and reactive oxygen species (ROS) generation. In vivo, acute seizure protection was assessed in the pentylenetetrazol (PTZ) model, and antiepileptogenic efficacy was tested in the kainic acid‐induced status epilepticus (KA‐SE) model using chronic video‐electrocorticographic recordings. Behavioral outcomes relevant to epilepsy‐associated comorbidities, including anxiety‐like behavior and exploratory activity, were also examined. Results: Cemdomespib reduced epileptiform calcium oscillations, stabilized mitochondrial membrane potential, and suppressed ROS generation in vitro. In the PTZ model, 45% of pretreated animals were protected from seizures, and those that seized exhibited reduced severity, shorter duration, and delayed onset. In the KA‐SE model, cemdomespib significantly mitigated the severity of SE and reduced the emergence of spontaneous recurrent seizures during the chronic phase, as evidenced by lower seizure frequency, decreased cumulative seizure burden, and prolonged latency to seizure onset. Furthermore, treated animals demonstrated improved anxiety‐like behavior and enhanced exploratory activity. Significance: Cemdomespib confers both acute seizure protection and long‐term suppression of epileptogenesis, likely through Hsp90‐dependent regulation of mitochondrial integrity and redox signaling. These findings highlight Hsp90 inhibition as a promising therapeutic strategy for seizure control while also mitigating the progression of epileptogenesis and its associated neurobehavioral impairments. [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 |
| FullText | Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 192955188 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Targeting Hsp90 with cemdomespib reduces seizure burden and alters disease course in preclinical epilepsy models. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Sheeni%2C+Yara%22">Sheeni, Yara</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Singh%2C+Prince+Kumar%22">Singh, Prince Kumar</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sandouka%2C+Sereen%22">Sandouka, Sereen</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Taige%22">Zhang, Taige</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nemirovski%2C+Alina%22">Nemirovski, Alina</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Saadi%2C+Aseel%22">Saadi, Aseel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Olowe+Taiwo%2C+Rhoda%22">Olowe Taiwo, Rhoda</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Walker%2C+Matthew+C%2E%22">Walker, Matthew C.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shekh‐Ahmad%2C+Tawfeeq%22">Shekh‐Ahmad, Tawfeeq</searchLink> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. Apr2026, Vol. 67 Issue 4, p1665-1678. 14p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Seizures+%28Medicine%29%22">Seizures (Medicine)</searchLink><br /><searchLink fieldCode="DE" term="%22Heat+shock+proteins%22">Heat shock proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Epilepsy%22">Epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroinflammation%22">Neuroinflammation</searchLink><br /><searchLink fieldCode="DE" term="%22Mitochondria%22">Mitochondria</searchLink><br /><searchLink fieldCode="DE" term="%22Oxidative+stress%22">Oxidative stress</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Objective: Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequent cognitive and psychiatric comorbidities. Although current antiseizure medications provide symptomatic relief, they fail to prevent or modify epileptogenesis. Heat shock protein 90 (Hsp90) is increasingly recognized as a regulator of neuroinflammatory and oxidative stress pathways implicated in seizure generation and disease progression. Here, we investigated the therapeutic potential of cemdomespib, a novel and selective Hsp90 inhibitor, across complementary preclinical models of epilepsy. Methods: In vitro, cemdomespib was evaluated in the low‐magnesium model of epileptiform activity for its effects on neuronal calcium dynamics, mitochondrial membrane stability, and reactive oxygen species (ROS) generation. In vivo, acute seizure protection was assessed in the pentylenetetrazol (PTZ) model, and antiepileptogenic efficacy was tested in the kainic acid‐induced status epilepticus (KA‐SE) model using chronic video‐electrocorticographic recordings. Behavioral outcomes relevant to epilepsy‐associated comorbidities, including anxiety‐like behavior and exploratory activity, were also examined. Results: Cemdomespib reduced epileptiform calcium oscillations, stabilized mitochondrial membrane potential, and suppressed ROS generation in vitro. In the PTZ model, 45% of pretreated animals were protected from seizures, and those that seized exhibited reduced severity, shorter duration, and delayed onset. In the KA‐SE model, cemdomespib significantly mitigated the severity of SE and reduced the emergence of spontaneous recurrent seizures during the chronic phase, as evidenced by lower seizure frequency, decreased cumulative seizure burden, and prolonged latency to seizure onset. Furthermore, treated animals demonstrated improved anxiety‐like behavior and enhanced exploratory activity. Significance: Cemdomespib confers both acute seizure protection and long‐term suppression of epileptogenesis, likely through Hsp90‐dependent regulation of mitochondrial integrity and redox signaling. These findings highlight Hsp90 inhibition as a promising therapeutic strategy for seizure control while also mitigating the progression of epileptogenesis and its associated neurobehavioral impairments. [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: BibEntity: Identifiers: – Type: doi Value: 10.1002/epi.70074 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 14 StartPage: 1665 Subjects: – SubjectFull: Seizures (Medicine) Type: general – SubjectFull: Heat shock proteins Type: general – SubjectFull: Epilepsy Type: general – SubjectFull: Neuroinflammation Type: general – SubjectFull: Mitochondria Type: general – SubjectFull: Oxidative stress Type: general Titles: – TitleFull: Targeting Hsp90 with cemdomespib reduces seizure burden and alters disease course in preclinical epilepsy models. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Sheeni, Yara – PersonEntity: Name: NameFull: Singh, Prince Kumar – PersonEntity: Name: NameFull: Sandouka, Sereen – PersonEntity: Name: NameFull: Zhang, Taige – PersonEntity: Name: NameFull: Nemirovski, Alina – PersonEntity: Name: NameFull: Saadi, Aseel – PersonEntity: Name: NameFull: Olowe Taiwo, Rhoda – PersonEntity: Name: NameFull: Walker, Matthew C. – PersonEntity: Name: NameFull: Shekh‐Ahmad, Tawfeeq IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 04 Text: Apr2026 Type: published Y: 2026 Identifiers: – Type: issn-print Value: 00139580 Numbering: – Type: volume Value: 67 – Type: issue Value: 4 Titles: – TitleFull: Epilepsia (Series 4) Type: main |
| ResultId | 1 |
