Research Article Open Access Saraswathy et al., J Mol Biomark Diagn 2014, 6:4 DOI: 10.4172/2155-9929.1000241 Volume 6 • Issue 4 • 1000241 J Mol Biomark Diagn ISSN:2155-9929 JMBD an open access journal *Corresponding author: Dr. Saraswathy G.R., Department of Pharmacology, M.S. Ramaiah University of Applied Sciences, Bangalore, Karnataka, India, Tel: 08123230400; Fax: 080-23607488; E-mail: saraswathypradish@gmail.com Received July 08, 2015; Accepted July 28, 2015; Published July 31, 2015 Citation: Saraswathy GR, Maheswari E, Santhrani T (2015) Protective Effect of Alpha Lipoic Acid against Phenytoin Induced Behavioral Abnormalities in Rats. J Mol Biomark Diagn 5: 241. doi:10.4172/2155-9929.1000241 Copyright: © 2015 Saraswathy GR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Keywords: Phenytoin; Alpha lipoic acid; Oxidative stress; Behavioral abnormalities Introduction Epileptic disorders afect approximately 0.5-1% of human population [1]. Te main goal in the treatment of epilepsy is to attain a complete control over seizures without potential side efects to improve the quality of life. Phenytoin is a most common and efective antiepileptic drug (AED) prescribed for a prolonged period to achieve seizure control in all types of generalized as well as partial seizures and status epilepticus [2]. Phenytoin causes several serious side efects notably neurotoxicity [3]. Tis drug generates reactive oxygen species during its metabolism leading to severe oxidative stress which in turn results in neuro-degeneration. Long term phenytoin therapy causes cerebellar degeneration [4] resulting in cognitive impairment [5], ataxia, nystagmus and slurred speech [6]. Alpha-lipoic acid (ALA) also known as thioctic acid (TA), is essential for the function of diferent enzymes of oxidative metabolism [7,8]. ALA was initially used in the treatment of acute poisoning with amanita phalloides, deadly poison followed by its application in treating neuropathic complaints [9]. It is believed that ALA or its reduced form, dihydrolipoic acid (DHLA) possess a number of biochemical functions acting as biological antioxidants, as metal chelators, reducing the oxidized forms of other antioxidant agents such as vitamin C and E and glutathione (GSH). ALA has also shown to improve endothelial dysfunction [10] and to reduce oxidative stress post exercise training [11]. It also protects against the development of atherosclerosis and inhibits the progression of an already established atherosclerosis plaque [12,13]. Tese above-mentioned benefts have insisted the use of ALA as a potential therapeutic agent for many chronic diseases with great epidemiological as well as economic and social impact such as diabetes mellitus (DM) and its complications [14,15], hypertension [16], Alzheimer’s disease (AD) [17], Down syndrome [18], cognitive dysfunction and some types of cancer [19]. ALA is recommended as a dietary supplement in medical and nutritional management of patients. Te therapeutic or toxic efects of phenytoin depend on its serum concentration. Te serum levels of phenytoin were estimated at the end of the study period afer the steady state of the drug was achieved to investigate if there were any pharmacokinetic interactions between phenytoin and ALA. Pharmacodynamic interference of ALA over antiepileptic protection ofered by phenytoin was also studied. Our work is a preliminary study to assess the ameliorative efect of ALA against phenytoin induced behavioral abnormalities. Phenytoin and its metabolites are reported to induce oxidative stress in brain regions leading to behavioral abnormalities. Hence, we explored the ameliorative efect of ALA against phenytoin induced behavioral abnormalities like impaired cognition, exploratory behavior, spontaneous motor activity and locomotor activity in addition to the estimation of regional brain lipid peroxidation and acetyl cholinesterase Protective Effect of Alpha Lipoic Acid against Phenytoin Induced Behavioral Abnormalities in Rats Saraswathy GR 1 *, Maheswari E 2 and Santhrani T 3 1 Department of Pharmacology, M.S. Ramaiah University of Applied Sciences, Karnataka, India 2 Department of Pharmacy Practice, M.S. Ramaiah University of Applied Sciences, Karnataka, India 3 Department of Pharmacology, Institute of Pharmaceutical Technology, Sri Padmavathi Mahila Visvavidyalayam, Andhra Pradesh, India Abstract Background: Long term administration of antiepileptic drug phenytoin is reported to cause behavioral abnormalities mediated via oxidative stress. The effect of an antioxidant alpha lipoic acid (ALA) against phenytoin induced behavioral abnormalities was investigated. Methods: The study was carried out in albino wistar rats. The rats were divided into fve groups of six animals each. Group 1 received 0.2% carboxy methyl cellulose (CMC, p.o), group 2 received 20 mg/kg phenytoin (p.o), groups 3,4 and 5 received 50, 100 and 200 mg/kg (p.o) of ALA in 0.2% CMC, respectively 1 h prior to phenytoin for 45 days. Motor coordination, exploratory behavior, memory and spontaneous motor activity were evaluated by Rota rod, Hole board, Elevated plus maze and Actophotometer respectively. On day 45, regional brain lipid peroxidation and acetylcholinesterase (ACh E) activity along with brain histopathological investigation were performed after euthanasia. In addition, pharmacokinetic and pharmacodynamic drug interactions between phenytoin and ALA were also studied. Results: Long term administration of phenytoin showed behavioral abnormalities, increased regional brain malondialdehyde (MDA) and ACh E activity. The histopathological investigation showed congested and damaged cells in brain regions. ALA substantially reversed phenytoin induced behavioral abnormalities, oxidative stress and alleviated the histopathological abnormalities. There were no signifcant differences in the serum levels of phenytoin and the degree of protection offered by phenytoin in ALA supplemented groups revealing that there were no pharmacokinetic and pharmacodynamic interactions between phenytoin and ALA. Conclusion: This study reports the effectiveness of ALA against phenytoin induced behavioral abnormalities and oxidative stress in rats without altering the bioavailability of phenytoin and its therapeutic effect. Journal of Molecular Biomarkers & Diagnosis J o u r n a l o f M o l e c u l a r B i o m a r k e r s & D i a g n o s i s ISSN: 2155-9929