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EFFECTS OF CHRONIC ADMINISTRATION OF EFAVIRENZ
ON THE BRAIN AND INFERIOR COLLICULUS WEIGHTS
OF ADULT WISTAR RATS
J. O. Adjene, F. I. Arukwe.
Department of Anatomy. School of Basic Medical Sciences. University of Benin.
Edo State, Nigeria
joadjene @ yahoo.com
Rev Electron Biomed / Electron J Biomed 2009;3:36-40
Comment of the reviewer José María Trejo Gabriel y Galán. MD, PhD. Jefe de Neurología del Hospital General Yagüe - Complejo Asistencial de Burgos. Burgos. España.
Comment of the reviewer Prof. D. José María Eirós Bouza. MD, PhD.. Titular de Microbiología de la Facultad de Medicina de la Universidad de Valladolid. Valladolid. España.
SUMMARY:
The effects of chronic administration of Efavirenz commonly used as part of highly active antiretroviral therapy (HAART) for the treatment of Human Immunodeficiency Virus (HIV) type-1 on the weight of the brain and inferior colliculus of adult wistar rats was carefully studied. The rats of both sexes (n=16), with an average weight of 200g were randomly assigned into treatment (n=8) and control (n=8) groups.
The rats in the treatment group received 600 mg/70 kg body weight of Efavirenz dissolved in distilled water daily for 30 days (thirty days) through the orogastric tube. The control group received equal volume of distilled water daily for 30 days through the same route. The rats were fed with grower's mash obtained from Edo Feeds and Flour Mill Limited, Ewu, Edo state, Nigeria and given water liberally. The rats were sacrificed by cervical dislocation method on the thirty-first day of the experiment and the brains were carefully dissected out, dried, weighed and recorded using the Mettler Toledo weighing balance.
The findings indicate that there was a significant decrease (P < 0.05) in the dry brain weight and an increase in the relative dry brain weight of the treatment group as compared with the control group in this experiment. There was also a significant increase (P < 0.05) in the weight of the dry inferior colliculus per total dry brain weight in the treatment group when compared with the control group. However, the relative dry inferior colliculus weight was significantly higher (P < 0.05) in the treatment group also than that of the control group in this experiment
KEY WORDS: Efavirenz. Wistar Rats. Brain. Inferior Colliculus.
RESUMEN: EFECTOS DE LA ADMINISTRACIÓN CRÓNICA DE EFAVIRENZ EN EL PESO DEL CEREBRO Y COLÍCULIO INFERIOR DE RATAS WISTAR ADULTAS.
Los efectos de la administración crónica de Efavirenz comúnmente utilizados como parte de la terapia antirretroviral altamente activa (HAART) para el tratamiento del Virus de Inmunodeficiencia Humana (VIH) tipo-1 en el peso del cerebro y colículo inferior de adultos ratas Wistar han sido cuidadosamente estudiados. Ratas de ambos sexos (n = 16), con un peso promedio de 200 g fueron asignadas aleatoriamente a dos grupos, uno de tratamiento (n = 8) y otro control (n = 8).
Las ratas del grupo de tratamiento recibieron diariamente 600 mg/70 kg de peso de Efavirenz disuelto en agua destilada durante 30 días a través de una sonda gástrica. El grupo control recibió un volumen igual de agua destilada diariamente, durante 30 días por la misma vía. Las ratas fueron alimentadas con pienso obtenido a partir de alimentos de la casa Edo Feeds and Flour Mill Limited, Ewu, Edo state, Nigeria y bebieron agua libremente. Los animales se sacrificaron por el método de la dislocación cervical en el trigésimo primer día del experimento y el cerebro se extrajo cuidadosamente, siendo secado, pesado y grabado con la balanza Mettler Toledo.
Los resultados indican que hubo una disminución significativa (P <0,05) en el peso seco del cerebro y un aumento en el peso relativo del cerebro seco del grupo de tratamiento en comparación con el grupo control en este experimento (cuadro 1, figuras 1 y 2). También hubo un incremento significativo (P <0,05) en el peso seco del colículo inferior al peso total seco del cerebro en el grupo de tratamiento en comparación con el grupo control. Sin embargo, la relación peso seco colículo inferior fue significativamente mayor (P <0,05) en el grupo de tratamiento también diferente a la del grupo de control en este experimento(cuadro 1, figura 3).
PALABRAS CLAVE: Efavirenz. Ratas Wistar. Cerebro. Colliculus Inferior.
INTRODUCTION
Efavirenz is an antiretroviral drug that belongs to the class of drugs called non-nucleoside reverse transcriptase inhibitor (NNRTI) used as part of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) type-11. Efavirenz has been found to be effective in many combination regimes for the treatment of HIV infection, both in previously untreated and in treated individuals. It has been combined successfully with nucleoside consisting of lamivudine or emtricitabine plus abacavir, didanosine, stavidine, tenofovir or zidovudine to achieve virologic suppression in a high percentage of recipients2,3. Most antiviral agents do not efficiently penetrate the blood brain barrier (BBB) or are actively transported out of the central nervous system4. Even after antiviral treatment that successfully controls virus in the treatment compartments, the central nervous system may suffer continuing damage induced by HIV infection5. Efavirenz may be taken once a day without regards to meal and it can penetrate the central nervous system and spinal fluids6,7.
Some adverse effect in the central nervous system has been commonly associated with efavirenz8. The most common central nervous system effects include confusion, insomnia, abnormal vivid dreams, dizziness and headache. Efavirenz has emerged as cornerstone of highly active antiretroviral therapy (HAART) regimens. The side effect profile of the drug is generally regarded as satisfactory. However, there are conflicting study results in the medical literature as well as conflicting studies from patients and physicians regarding the neuropsychiatric problems associated with efavirenz9. Lipodystrophy, moderate or severs pain, abnormal vision, arthralgia, asthenia, dyspnea, gynecomastia, myalgia, myopathy and tinnitus have been reported concerning efavirenz1.
The inferior colliculus is the obligatory midbrain synaptic target of the ascending auditory pathway, in which the contralateral ear is represented primarily10. Inferior colliculus is essential for normal hearing and for the startle reflex. It receives its ascending input mainly from the contralateral cochlear nucleus and the superior olive and sends axons to the medial geniculate body10.
Cortical structures such as the medial and lateral geniculate bodies, inferior and superior colliculi have higher glucose utilization than other structures11. There is a correlation between functional activity and metabolic rate such as in the visual and auditory system11. Since efavirenz crosses the blood brain barrier, it is relevant to investigate its effect on the brain and inferior colliculus. It is probable that the adverse effects of efavirenz on hearing such as tinnitus may be due to direct effect of efavirenz on the inferior colliculus. This present study was to elucidate the effects of chronic administration of efavirenz on the weight of the brain and inferior colliculus of the adult wistar rats.
MATERIALS AND METHODS
ANIMALS: Sixteen adult wistar rats of both sexes with average weight of 200g were randomly assigned into two groups; control (n=8) and treatment (n=8). The rats were obtained and maintained in the Animal Holding of the Department of Anatomy, School of Basic Medical Sciences, University of Benin, Benin City, Edo State Nigeria. They were fed with grower's mash obtained from Edo Feeds and Flour Mill Limited, Ewu, Edo State, Nigeria and given water liberally. Efavirenz was obtained from the PEPFAR unit, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria.
DRUG ADMINISTRATION: The rats in the treatment group received the recommended dosage of 600mg/70kg body weight of efavirenz dissolved in distilled water for thirty days through orogastric tube administration while the control rats received equal volume of distilled water through the same route and for the same period. The body weights of both groups were measured using Mettler Toledo weighing balance before and during the period of treatment.
DISSECTION OF THE BRAIN AND THE INFERIOR COLLICULUS: The rats in both groups were sacrificed by cervical dislocation and the skull was quickly opened with the aid of a pair of bone forceps to expose the brain. The brain was dried, weighed and recorded. The inferior colliculi were carefully dissected out, weighed and also recorded using the Mettler Toledo weighing balance.
STATISTICAL ANALYSIS: The mean values of the brain and inferior colliculus obtained from the control and treatment groups were recorded and compared statistically using the paired sample T-Test and Symmetric Measured Test of the Statistical Package for Social Sciences (SPSS)
RESULTS
BRAIN WEIGHT: There was a significant decrease (P < 0.05) in the brain weight of the treatment group as compared to that of the control group in this experiment. However, the relative brain weight of the treatment group was significantly higher (P < 0.05) than that of the control group when compared statistically (Table 1, figures 1 and 2).
Table 1: The Mean Weight (g) and Relative Weight (%) of the Brain and Inferior Colliculus (IC) of the Animals.
 Figure 1: Bar Chart Showing the Brain Weight (g) of the Animals |
 Figure 2: Bar Chart Showing the Relative Brain Weight (%) of the Animals |
INFERIOR COLLICULUS WEIGHTS: There was a significant increase (P < 0.05) in the dry weight of the inferior colliculus per the total dry brain weight in the treatment group as compared to the control group. The relative inferior colliculus weight was also significantly higher (P < 0.05) in the treatment group than that of the control group in this experiment (Table 1, fig. 3 & 4)
 Figure 3: Bar Chart Showing the Inferior Colliculus Weight (g) of the Animals |  Figure 4: Bar Chart Showing the Relative Inferior Colliculus Weight (%) of the Animals |
DISCUSSION
The result of this experiment revealed that chronic administration of efavirenz showed a significant decrease (P > 0.05) in the brain weight of the treatment group as compared to that of the control group in this experiment. However, the relative brain weight of the treatment group was significantly higher (P < 0.05) than that of the control group when compared statistically (Table 1, fig 1 & 2). The inferior collicullus weight of the treatment group was significantly higher (P 0.05) than that of the control group. The relative inferior colliculus weight of the treatment group was also significantly higher (P < 0.05) than that of the control group in this experiment (Table 1, fig. 3 & 4)
It has been reported that chronic administration of chloroquine affects the weight of the inferior collilculus in adult wistar rats12. Ischemic or pharmacologic disruption of cellular transporters can cause swelling of the brain parenchyma. Under such conditions, there is a net shift of water from the extracellular space to the interior of the brain cells13. Cytotoxic edema usually involves intracellular swelling of glial, endothelia and neurons 13. The weight of the inferior colliculus and the relative brain weight reported in this experiment to be significantly increased might due to neurotoxic effect of efavirenz on the cells of the brain and inferior collicus of the adult wistar rats.
There was a significant increase (P < 0.05) in the weight of the inferior colliculus and the relative brain weight in the treatment group as compared to the control group in this experiment. Regulation of brain water content and therefore of the volume is critical for maintaining the intracranial pressure within tolerable limits13. In this study efavirenz could have acted as toxins to the cell of the inferior colliculus and the relative brain weight thus affecting their cellular integrity and causing a defect in membrane permeability and cell volume homeostasis. Efavirenz is known to cross blood brain barrier and thus getting access to the cells of the brain. The prime candidates for inducing the massive cell increase observed in neurodegeneration are neurotoxins14.
As brain tissue swells or shrinks as seen in this study, the activity of the cellular transporters is approximately modified by the up or down regulations as earlier reported in the case of hyponatramia or hypernatremia13. Ischemia or pharmacologic disruption of cellular transporters can cause swelling of parenchyma of the brain and that of the inferior colliculus. The pharmacologic disruption of the brain and inferior colliculus weights caused by efavirenz is a cardinal feature of the results of this experiment. Though there are many different causes of cell swelling, including drug poisoning, water intoxication, hypoxia, and acute hyponatremia13. Under such conditions there is a net shift of water from the extracellular space to the interior of the brain cells13. The significant increase associated with the inferior colliculus and the relative brain weight in this experiment usually involves intracellular swellings of glial, endothelia and neurons13. Brains swelling attendant to severe cytotoxic edema may lead to marked reduction in the size of the ventricular system and basal cisterns13.
The increase in weight observed in the treated relative brain weight and that of the inferior colliculus may be due to efavirenz interference. The toxic effects of efavirenz on the brain and inferior colliculus weights of the treated animals observed in this experiment may underline the possible neurological symptoms, such as tinnitus as reported following efavirenz treatment1.
REFERENCES
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CORRESPONDENCE:
Dr. J.O.Adjene
Department of Anatomy. School of Basic Medical Sciences. University of Benin.
Edo State, Nigeria
E-mail: joadjene @ yahoo.com