The antiepileptic medications carbamazepine and phenytoin inhibit native sodium currents in murine osteoblasts

Abstract

SUMMARYObjective: 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 (Na V ) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on Na V 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 Na V . Whole-cell patch-clamp recordings were made to identify the native currents expressed and to assess the actions of carbamazepine (50 lM) or phenytoin (50 lM). Results: Na V 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 AE 5.9%, n = 9; p < 0.001), and for phenytoin (35.5 AE 6.9%, n = 7; p < 0.001). Significance: Mouse osteoblasts express Na V , and native Na V currents are blocked by carbamazepine and phenytoin, supporting our hypothesis that AEDs can directly influence osteoblast function and potentially affect bone strength.

Impaired bone and muscle development in young people treated with antiepileptic drugs

“…Animal model work demonstrates a direct effect of carbamazepine and phenytoin on voltagegated sodium channels within osteoblasts, 37 which may explain the observed reduction in bone density. Animal model work demonstrates a direct effect of carbamazepine and phenytoin on voltagegated sodium channels within osteoblasts, 37 which may explain the observed reduction in bone density.…”

“…The possibility of a direct effect of AEDs on reducing bone formation remains. Animal model work demonstrates a direct effect of carbamazepine and phenytoin on voltagegated sodium channels within osteoblasts, 37 which may explain the observed reduction in bone density. However, data for other ion channels, other AEDs, and secondary pathways are still required.…”

Osteoporose und Frakturrisiko bei Epilepsie und antiepileptischer Therapie

“…Antiepileptika können auch ohne Vitamin D-Defizienz auf den Knochen ungünstig wirken. Als mögliche Mechanismen werden eine verminderte intestinale Kalziumabsorption (PHT), eine Parathormonresistenz (CBZ), eine Calcitonin-Defizienz (PHT, Primidon), eine Störung des Vitamin-K-Stoffwechsels (PHT) und eine direkte Medikamentenwirkung auf Knochenzellfunktionen (PHT, CBZ, VPA) vermutet [4,36]. Andere, indirekte Arzneimittelwirkungen wie hormonelle Veränderungen (z.…”

Automated Planar Patch-Clamp Recording of P2X Receptors

“…required. As an example, medium resistance chip are ideal for use with HEK293 cells and CHO cells [16,22] and high resistance chips are ideal for use with mouse osteoblasts [23]. For example, if cells are very small, they will pass through a low resistance chip hole when suction is applied, and conversely, large cells will not form good seals on high resistance chips.…”