A Flupirtine Benzyl Carbamate Improves Neurocognitive Deficits and Molecular Pathology in the Cln6nclf Mouse

Authors

Victoria Chaoul, American University of Beirut Medical Center
Omar Shmoury, American University of Beirut Medical Center
Ramy Alam, American University of Beirut Medical Center
Sara Saab, American University of Beirut Medical Center
Joelle Makoukji, American University of Beirut Medical Center
Lynn Al Aridi, American University of Beirut Medical Center
Nadine J. Makhoul, American University of Beirut Medical Center
Jihane Soueid, American University of Beirut
Angelica V. Carmona, University of Nebraska Medical Center
Princess Simeon, University of Nebraska Medical CenterFollow
Paul C. Trippier, University of Nebraska Medical CenterFollow
Rose-Mary Boustany, American University of Beirut Medical Center

Document Type

Article

Journal Title

Cells

Publication Date

2026

Volume

15

Abstract

Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6^nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in locomotor hyperactivity and recovery of visuospatial performance. In the brains of male and female Cln6^nclf mice, flupirtine benzyl carbamate significantly decreased astrocytosis, microgliosis and mitochondrial ATP synthase subunit C (SCMAS) accumulation, increased neuronal marker expression and reduced the number of TUNEL-positive cells. The treatment failed to rescue photoreceptor loss or clear retinal SCMAS storage. These outcomes result in distinct sex-specific differences in neuronal vulnerability and drug responsiveness. Overall, these findings demonstrate that flupirtine benzyl carbamate diminishes key motor, visual and pathological deficits in CLN6 disease, highlighting its promise as a potential disease-modifying therapy for CLN6 in humans despite sex-specific differences

MeSH Headings

Animals, Neuronal Ceroid-Lipofuscinoses, Mice, Female, Male, Carbamates, Aminopyridines, Disease Models, Animal, Brain

DOI Link

10.3390/cells15050442

ISSN

2073-4409

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Chaoul, Victoria; Shmoury, Omar; Alam, Ramy; Saab, Sara; Makoukji, Joelle; Aridi, Lynn Al; Makhoul, Nadine J.; Soueid, Jihane; Carmona, Angelica V.; Simeon, Princess; Trippier, Paul C.; and Boustany, Rose-Mary, "A Flupirtine Benzyl Carbamate Improves Neurocognitive Deficits and Molecular Pathology in the Cln6nclf Mouse" (2026). Journal Articles: Pharmaceutical Sciences. 53.
https://digitalcommons.unmc.edu/cop_pharmsci_articles/53