Protective Effect of Alpha Lipoic Acid against Phenytoin Induced Behavioral Abnormalities in Rats

Abstract

IntroductionEpileptic disorders affect approximately 0.5-1% of human population [1]. The main goal in the treatment of epilepsy is to attain a complete control over seizures without potential side effects to improve the quality of life. Phenytoin is a most common and effective 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 effects notably neurotoxicity [3]. This 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 different 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]. These above-mentioned benefits 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] The therapeutic or toxic effects of phenytoin depend on its serum concentration. The serum levels of phenytoin were estimated at the end of the study period after 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 offered by phenytoin was also studied.Our work is a preliminary study to assess the ameliorative effect 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 effect 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 AbstractBackground: 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 induc...

Alpha-lipoic acid enhances short-term spatial memory of mice in open-space forced swim-induced depression mouse model

“…Previously, Nádia et al (2018) found that ALA 200 mg/kg reversed the deficits in short-term memory in CORT-induced depressive-like behaviour and cognitive deficits using NORT. Furthermore, Saraswathy et al (2015) found that, in a dose-dependent fashion, ALA (at doses 50, 100 and 200 mg/kg) reversed phenytoin-induced memory impairment of rats subjected to the elevated plus-maze test. The possible mechanism might be the prevention of alterations in insulin signalling, thereby decreasing memory impairment by increasing vesicular glutamate transporter 1 (VGlut 1), which was found impaired in the frontal regions of HFF Alzheimer's rats with a decline in cognition (Rodriguez-perdigon et al, 2016).…”