Exogenous Flupirtine as Potential Treatment for CLN3 Disease
CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate der...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/8/1872 |
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| author | Katia Maalouf Joelle Makoukji Sara Saab Nadine J. Makhoul Angelica V. Carmona Nihar Kinarivala Noël Ghanem Paul C. Trippier Rose-Mary Boustany |
| author_facet | Katia Maalouf Joelle Makoukji Sara Saab Nadine J. Makhoul Angelica V. Carmona Nihar Kinarivala Noël Ghanem Paul C. Trippier Rose-Mary Boustany |
| author_sort | Katia Maalouf |
| collection | DOAJ |
| description | CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in <i>Cln3<sup>Δex7/8</sup></i> mice. WT/<i>Cln3<sup>Δex7/8</sup></i> mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in <i>Cln3<sup>Δex7/8</sup></i> mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in <i>Cln3<sup>Δex7/8</sup></i> mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female <i>Cln3<sup>Δex7/8</sup></i> mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in <i>Cln3<sup>Δex7/8</sup></i> mice, paving the way for potential therapies for CLN3 disease. |
| first_indexed | 2024-03-10T17:40:03Z |
| format | Article |
| id | doaj.art-a2bef69d6b734d34b5e6c96c27a64668 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T17:40:03Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a2bef69d6b734d34b5e6c96c27a646682023-11-20T09:44:15ZengMDPI AGCells2073-44092020-08-0198187210.3390/cells9081872Exogenous Flupirtine as Potential Treatment for CLN3 DiseaseKatia Maalouf0Joelle Makoukji1Sara Saab2Nadine J. Makhoul3Angelica V. Carmona4Nihar Kinarivala5Noël Ghanem6Paul C. Trippier7Rose-Mary Boustany8Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, LebanonDepartment of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, LebanonDepartment of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, LebanonDepartment of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, LebanonDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6120, USADepartment of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USADepartment of Biology, American University of Beirut, Beirut 1107 2020, LebanonDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6120, USADepartment of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, LebanonCLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in <i>Cln3<sup>Δex7/8</sup></i> mice. WT/<i>Cln3<sup>Δex7/8</sup></i> mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in <i>Cln3<sup>Δex7/8</sup></i> mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in <i>Cln3<sup>Δex7/8</sup></i> mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female <i>Cln3<sup>Δex7/8</sup></i> mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in <i>Cln3<sup>Δex7/8</sup></i> mice, paving the way for potential therapies for CLN3 disease.https://www.mdpi.com/2073-4409/9/8/1872sphingolipidsneurodegenerationceramideCLN3 disease<i>Cln3<sup>Δex7/8</sup></i> miceflupirtine |
| spellingShingle | Katia Maalouf Joelle Makoukji Sara Saab Nadine J. Makhoul Angelica V. Carmona Nihar Kinarivala Noël Ghanem Paul C. Trippier Rose-Mary Boustany Exogenous Flupirtine as Potential Treatment for CLN3 Disease Cells sphingolipids neurodegeneration ceramide CLN3 disease <i>Cln3<sup>Δex7/8</sup></i> mice flupirtine |
| title | Exogenous Flupirtine as Potential Treatment for CLN3 Disease |
| title_full | Exogenous Flupirtine as Potential Treatment for CLN3 Disease |
| title_fullStr | Exogenous Flupirtine as Potential Treatment for CLN3 Disease |
| title_full_unstemmed | Exogenous Flupirtine as Potential Treatment for CLN3 Disease |
| title_short | Exogenous Flupirtine as Potential Treatment for CLN3 Disease |
| title_sort | exogenous flupirtine as potential treatment for cln3 disease |
| topic | sphingolipids neurodegeneration ceramide CLN3 disease <i>Cln3<sup>Δex7/8</sup></i> mice flupirtine |
| url | https://www.mdpi.com/2073-4409/9/8/1872 |
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