Histomorphological Effects of Co-Administration of Efavirenz and Vitamin E on the Hippocampus of Wistar Rats

Efavirenz is an oral non-nucleotide reverse transcriptase inhibitor (NNRTI) used as a part of highly active antiretroviral therapy (HAART) for the treatment of type 1 human immunodeficiency virus (HIV-1). Thirty Wistar Rats of weight 140 g–192 g were used for the study. The rats were divided into six treatment groups. Control (group) A were administered with 1 ml of distil water; group B were administered with 8.57mg/kg body weight of Efavirenz ; group C were administered with Double dose of 17.14 mg/kg body weight of Efavirenz; group D were administered with Triple dose of 25.71 mg/kg body weight of Efavirenz; group E were administered with 8.57mg/kg body weight of Efavirenz and 14.82 mg/kg body weight of Vitamin E; and group F were administered with 14.82 mg/kg body weight of Vitamin E. drug administration lasted for 32 days. The animals were handled according to the guidelines for the treatment of laboratory animals. On the 33rd day, the rats were sacrificed using chloroform inhalation method. The hippocampi were excised, routinely processed, stained using haematoxylin and eosin method, and viewed in DPX medium under light microscope. Findings revealed that the percentage change in body weight was higher in rats treated with EFV and approximately normal in rats treated with a combination of EFV and Vitamin E when compared with the control animals. The hippocampus of Wistar rats administered with efavirenz, showed distortions and neurodegeneration in the cell layers; the pyramidal cells were shrunken with various degree of vacoulations. In the group where efavirenz was combined with viamen E this changes were slightly ameliorated. The cells of the polymorphic (PM) pyramidal and molecular (M) layers appeared normal in the control groups A and group F. Efavirenz administration can damage the hippocampus. Vitamin E has the potential of ameliorating this effect. Therefore, Vitamin E should be prescribed for patients on efavirenz administration. © 2015 iGlobal Research and Publishing Foundation. All rights reserved. Indo Global Journal of Pharmaceutical Sciences, 2015; 5(3): 192-198 193 greater risk for adverse effects from efavirenz due to decreased drug clearance [7]. Most antiviral agents do not efficiently penetrate the blood brain barrier or are actively transported out of the central nervous system. Hence, even after antiviral treatment that successfully controls virus in the treatment compartments, the central nervous system may suffer continuing damage induced by HIV infection. Efavirenz is one of the HAART agents that can penetrate the central nervous system and spinal fluids with a capacity to strongly inhibit multi-drug resistant proteins [8-14]. Thus, efavirenz has emerged as cornerstone of most HIV regimens [15]. The following nervous system disorders have been reported with the use of efavirenz; abnormal dreams, disturbance in attention, dizziness, headache, insomnia, somnolence, agitation, amnesia, ataxia, epilepsy, abnormal coordination, confusional state, convulsions, and abnormal thinking [4, 16-18]. It is known that efavirenz has the potential to cause toxicity in the central nervous system, but this is yet to be elucidated [19]. In cellular necrosis, the rate of progression depends on the severity of the environmental insults. The prime candidates for inducing the massive cell destruction observed in neurodegeneration are neurotoxins. These may be substances present in small amounts in the environment, or even naturally occurring chemicals such as glutamate used by the brain as transmitter's substances. The latter when present at a critical level can be toxic to the brain cells in which they normally excite [20]. Prolonged administration of efavirenz has been reported to cause toxic effects on the lateral geniculate body [4]. Less common side-effects of efavirenz include headache, alcohol intolerance, fever, aches, pains and fatigue, fluid retention in the hands and feet, dry mouth, elevated lipid levels, pancreatitis, skin problems, asthma and changes to vision and taste. Interestingly, reports of lipid elevations have included rises in high-density lipoprotein (HDL) or ‘good’ cholesterol, particularly in people with a genetic polymorphism in the multidrug resistance gene [21, 22]. However, levels of total cholesterol also increase, resulting in a small net increase in the ratio of total to HDL cholesterol [23]. This study also found that efavirenz causes elevations in triglyceride levels. Vitamin E is the collective name for a group of fat-soluble compounds with distinctive antioxidant activities [24]. Naturally occuring Vitamin E exists in eight different forms: alpha-, beta-, gamma-, and delta-tocopherol; and alpha-, beta-, gamma-, and delta-tocotrienol. Although tocopherols and tocotrienols are available from the diet, alpha-tocopherol is the most active form in humans [24]. The liver metabolizes and excretes the other vitamin E forms but preferentially resecretes alphatocopherol via the hepatic alpha-tocopherol transfer protein. As a result, blood and cellular concentrations of other forms of vitamin E are lower than those of alphatocopherol. Vitamin E has many biological functions, the antioxidant function being the most important and best known. Other functions include enzymatic activities, gene expression, and neurological function(s) [24]. Another important function of vitamin E has been suggested in cell signaling. Some studies have suggested that tocotrienols have specialized roles in protecting neurons from damage [25] and cholesterol reduction. Oral consumption of tocotrienols is also thought to protect against strokeassociated brain damage. There is some evidence that allrac alpha-tocopherol (man-made vitamin E) is effective for slowing cognitive function decline in people with moderately severe Alzheimer's disease. This study therefore was designed to investigate the effect of combined administration of Vitamin E and efavirenz on the histology of the hippocampus of Wistar rats.