Homocysteine and Apoptotic Factors in Epileptic Patients Treated with Anti-Epileptic Drugs

An elevated plasma homocysteine (Hcy) level is an established risk factor for many diseases such as vascular disease, neurodegenerative diseases, and fetal developmental defects. The literature data indicate that therapy with antiepileptic drugs (AEDs) may induce numerous plasma molecular changes, including an increase in the concentration of Hcy and apoptotic factors. Hyperhomocysteinemia (HHcy) occurs in 10-40% of the epileptic population, and AEDs pharmacotherapy has a fundamental effect on the plasma Hcy level. Moreover, several studies have shown that Hcy may stimulate the apoptotic process of cells. One of the AEDs, valproic acid (VPA), may induce apoptosis in numerous neoplastic cell lines derived from leukemia, hepatic and gastric cancers, suggesting a potential anticancer drug effect. On the other hand, some studies have shown that VPA can also stimulate the anti-apoptotic Bcl-2 protein in neuronal cell lines, suggesting a potential neuroprotective role in the treatment of neurodegenerative diseases. This proor anti-apoptotic activity of VPA is dependent on the dose of the drug and the type of cell line, but further investigation is needed. * Corresponding author: Jolanta Dorszewska, MDs, PhD, Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 49 Przybyszewskiego Street, 60-355 Poznan, Poland. Phone: + 48 61 86 91 439; Fax: + 48 61 86 91 697; Email: dorszewskaj@yahoo.com No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Urszula Lagan-Jedrzejczyk, Margarita Lianeri, Wojciech Kozubski et al. 84 Our study of peripheral lymphocytes of 23 epileptic patients aged 18-69 and treated with AEDs demonstrated increased plasma Hcy levels, analyzed by high performance liquid chromatography (HPLC), no difference in expression of the apoptotic proteins p53, Bax, and Bcl-2, analyzed by the Western Blot method, and increased numbers of apoptotic cells, analyzed by flow cytometry. Analyses were completed before and during AEDs treatment in monotherapy with VPA, carbamazepine (CBZ) or lamotrigine (LTG), and in polytherapy, compared to 22 controls aged 22-61. Our results demonstrate an increased plasma Hcy level, greater than 16 μM, in epileptic patients treated with AEDs in monotherapy with VPA and CBZ, and in polytherapy. Moreover, in the epileptic patients with HHcy, we observed a lower expression of p53 protein, a higher level of Bax/Bcl-2 ratio, and an increased number of apoptotic cells compared to patients with a plasma Hcy level of less than 16 μM. Our conclusion is that some AEDs may generate HHcy, involving the apoptotic process in epileptic patients. The process by which apoptosis is induced by AEDs needs further study.