Anti-epileptic drugs inhibit viability of synoviocytes in vitro
More details
Hide details
Department of Rheumatology and Connective Tissue Diseases, Medical University, Lublin, Poland
Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland
Department of Orthopedics and Rehabilitation, Medical University, Lublin, Poland
Department of Toxicology, Institute of Rural Health, Lublin, Poland
Department of Medical Biology, Institute of Rural Health, Lublin, Poland
Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland
Corresponding author
Jolanta Parada-Turska   

Department of Rheumatology and Connective Tissue Diseases, Medical University, Lublin, Poland
Ann Agric Environ Med. 2013;20(3):571-574
The hyperplasia of synovial fibroblasts is considered to be essential for the evolution of joint destruction in rheumatoid arthritis (RA). Previously, we reported that anti-rheumatic drugs, both COX inhibitors and disease-modifying anti-rheumatic drugs inhibit proliferation of synoviocytes in vitro. The presented study investigates the effect of anti-epileptic drugs on the viability and proliferation of synovial fibroblasts in vitro.

Material and Methods:
Experiments were conducted on human synoviocytes derived from an RA patient and rabbit synoviocytes cell line HIG-82. Cell proliferation and viability were assessed by means of BrdU assay and MTT assay, respectively. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated.

Carbamazepine inhibited proliferation of human fibroblasts and viability of HIG-82 with IC50 values of 86 µM and 82 µM, respectively. Diphenylhydantoin, valproate and phenobarbital inhibited viability of HIG-82 cells with the IC50 values of 110, 500 and 1031 µM, respectively.

Based on these findings, it can be suggested that anti-epileptic drugs may have a disease-modifying effect on rheumatoid synovial proliferation.

Tobon GJ, Youinou P, Saraux A. The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis. J Autoimmun. 2010; 35: 10–14.
Mor A, Abramson SB, Pillinger MH. The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol. 2005; 115: 118–128.
Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006; 45: 669–675.
Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233: 233–255.
Parada-Turska J, Rzeski W, Majdan M, Kandefer-Szerszen M, Turski WA. Effect of glutamate receptor antagonists and antirheumatic drugs on proliferation of synoviocytes in vitro. Eur J Pharmacol. 2006; 535: 95–97.
Beutler AS, Li S, Nicol R, Walsh MJ. Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005; 76: 3107–3115.
Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010; 3: 5.
Parada-Turska J, Mitura A, Brzana W, Jablonski M, Majdan M, Rzeski W. Parthenolide inhibits proliferation of fibroblast-like synoviocytes in vitro. Inflammation. 2008; 31: 281–285.
Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949; 96: 99–113.
Georgescu HI, Mendelow D, Evans CH. HIG-82: an established cell line from rabbit periarticular soft tissue, which retains the “activatable” phenotype. In Vitro Cell Dev Biol. 1988; 24: 1015–1022.
Perez Martin JM, Fernandez FP, Labrador V, Hazen MJ. Carbamazepine induces mitotic arrest in mammalian Vero cells. Mutat Res. 2008; 637: 124–133.
Kwiecinska P, Wisniewska J, Gregoraszczuk EL. Effects of valproic acid (VPA) and levetiracetam (LEV) on proliferation, apoptosis and hormone secretion of the human choriocarcinoma BeWo cell line. Pharmacol Rep. 2011; 63: 1195–1202.
Meng QW, Zhao CH, Xi YH, Cai L, Sun LC, Sui GJ. [Enhancement of HER-2 degradation by carbamazepine in breast cancer SKBR-3 cell line]. Zhonghua Zhong Liu Za Zhi. 2006; 28: 503–506.
Stander M, Dichgans J, Weller M. Anticonvulsant drugs fail to modulate chemotherapy-induced cytotoxicity and growth inhibition of human malignant glioma cells. J Neurooncol. 1998; 37: 191–198.
Di DE, Mudge AW, Maycox PR. Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons. Bipolar Disord. 2005; 7: 33–41.
Basta-Kaim A, Budziszewska B, Leskiewicz M, Kubera M, Jagla G, Nowak W, et al. Effects of new antiepileptic drugs and progabide on the mitogen-induced proliferative activity of mouse splenocytes. Pharmacol Rep. 2008; 60: 925–932.
Freidkin I, Herman M, Tobar A, Chagnac A, Ori Y, Korzets A, et al. Effects of histone deacetylase inhibitors on rat mesangial cells. Am J Physiol Renal Physiol. 2010; 298: F426-F434.
Wang W, Liao XL, Chen JH, Li DD, Lin CL, Yan YX, et al. Sodium valproate induces mitochondria-dependent apoptosis in human hepatoblastoma cells. Chin Med J (Engl). 2011; 124: 2167–2172.
Machado MC, Bellodi-Privato M, Kubrusly MS, Molan NA, Tharcisio T, Jr., de Oliveira ER, et al. Valproic acid inhibits human hepatocellular cancer cells growth in vitro and in vivo. J Exp Ther Oncol. 2011; 9: 85–92.
Zhao X, Yang W, Shi C, Ma W, Liu J, Wang Y, et al. The G1 phase arrest and apoptosis by intrinsic pathway induced by valproic acid inhibit proliferation of BGC-823 gastric carcinoma cells. Tumour Biol. 2011; 32: 335–346.
Voisard R, Krebs R, Baur R, Hombach V. Valproic acid inhibits proliferation of human coronary vascular cells (SI/MPL-ratio: 0.5): a novel candidate for systemic and local therapy of postinterventional restenosis. Coron Artery Dis. 2010; 21: 286–291.
Sano M, Ohuchi N, Inoue T, Tono K, Tachikawa T, Kizawa Y, et al. Proliferative response to phenytoin and nifedipine in gingival fibroblasts cultured from humans with gingival fibromatosis. Fundam Clin Pharmacol. 2004; 18: 465–470.
Ohuchi N, Koike K, Sano M, Kusama T, Kizawa Y, Hayashi K, et al. Proliferative effects of angiotensin II and endothelin-1 on guinea pig gingival fibroblast cells in culture. Comp Biochem Physiol C Toxicol Pharmacol. 2002; 132: 451–460.
Genever PG, Cunliffe WJ, Wood EJ. Influence of the extracellular matrix on fibroblast responsiveness to phenytoin using in vitro wound healing models. Br J Dermatol. 1995; 133: 231–235.
Moy LS, Tan EM, Holness R, Uitto J. Phenytoin modulates connective tissue metabolism and cell proliferation in human skin fibroblast cultures. Arch Dermatol. 1985; 121: 79–83.
Goyle S. Effect of phenytoin on proliferation and differentiation of mouse muscle cells in vitro. Methods Find Exp Clin Pharmacol. 1983; 5: 143–148.
Hu X, Chen Z, Mao X, Tang S. Effects of phenytoin and Echinacea purpurea extract on proliferation and apoptosis of mouse embryonic palatal mesenchymal cells. J Cell Biochem. 2011; 112: 1311–1317.
Eadie MJ. Therapeutic drug monitoring—antiepileptic drugs. Br J Clin Pharmacol. 1998; 46: 185–193.
Warner A, Privitera M, Bates D. Standards of laboratory practice: antiepileptic drug monitoring. National Academy of Clinical Biochemistry. Clin Chem. 1998; 44: 1085-1095.
Journals System - logo
Scroll to top