The antiepileptic medications carbamazepine and phenytoin inhibit native sodium currents in murine osteoblasts
Corresponding Author
Sandra J. Petty
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Academic Centre, Ormond College, Parkville, Victoria, Australia
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Address correspondence to Sandra Petty, Department of Medicine, The University of Melbourne, 1st Floor, Kenneth Myer Building, Parkville, Vic. 3052, Australia. E-mail: [email protected]Search for more papers by this authorCarol J. Milligan
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Search for more papers by this authorMarian Todaro
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorKay L. Richards
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Search for more papers by this authorPamuditha K. Kularathna
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorCharles N. Pagel
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorChris R. French
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorElisa L. Hill-Yardin
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorTerence J. O'Brien
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorJohn D. Wark
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Bone and Mineral Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Search for more papers by this authorEleanor J. Mackie
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorSteven Petrou
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Search for more papers by this authorCorresponding Author
Sandra J. Petty
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Academic Centre, Ormond College, Parkville, Victoria, Australia
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Address correspondence to Sandra Petty, Department of Medicine, The University of Melbourne, 1st Floor, Kenneth Myer Building, Parkville, Vic. 3052, Australia. E-mail: [email protected]Search for more papers by this authorCarol J. Milligan
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Search for more papers by this authorMarian Todaro
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorKay L. Richards
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Search for more papers by this authorPamuditha K. Kularathna
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorCharles N. Pagel
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorChris R. French
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorElisa L. Hill-Yardin
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorTerence J. O'Brien
The Department of Medicine, Melbourne Brain Centre at The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorJohn D. Wark
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Bone and Mineral Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia
Search for more papers by this authorEleanor J. Mackie
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorSteven Petrou
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
Search for more papers by this authorSummary
Objective
Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage-gated sodium (NaV) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels.
Methods
Immunocytochemistry was performed on primary calvarial osteoblasts extracted from neonatal C57BL/6J mice and additional RNA sequencing (RNASeq) was included to confirm expression of NaV. Whole-cell patch-clamp recordings were made to identify the native currents expressed and to assess the actions of carbamazepine (50 μm) or phenytoin (50 μm).
Results
NaV expression was demonstrated with immunocytochemistry, RNA sequencing, and functionally, with demonstration of robust tetrodotoxin-sensitive and voltage-activated inward currents. Application of carbamazepine or phenytoin resulted in significant inhibition of current amplitude for carbamazepine (31.6 ± 5.9%, n = 9; p < 0.001), and for phenytoin (35.5 ± 6.9%, n = 7; p < 0.001).
Significance
Mouse osteoblasts express NaV, and native NaV currents are blocked by carbamazepine and phenytoin, supporting our hypothesis that AEDs can directly influence osteoblast function and potentially affect bone strength.
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