Hippocampus and Prefrontal Cortex Following the Use of Anti-Retroviral Therapy in Adult Wistar Rats: Therapeutic Role of Epigallocatechin Gallate
Click to view file (PDF)

How to Cite

Ogedengbe, O. O., Saliu, H., Fafure, A. A., Akintayo, C. O., Adekeye, A. O., Ajiboye, B. O., & Azu, O. O. (2022). Hippocampus and Prefrontal Cortex Following the Use of Anti-Retroviral Therapy in Adult Wistar Rats: Therapeutic Role of Epigallocatechin Gallate. Nigerian Journal of Physiological Sciences, 37(2), 207–214. https://doi.org/10.54548/njps.v37i2.7


The contribution of prefrontal-hippocampal interactions to brain function of people infected with HIV may be aggravated by toxicities due to long-term use of antiretroviral agents. This study was designed to investigate the curative potential of Epigallotatechin gallate (EGCG) in the treatment of neurodegenerative disorders as a possible consequence of antiretroviral toxicity. Twenty-four adult male Wistar rats, weighing 80~100g, were divided into four groups and treated as follows: control A (distilled water), B (HAART), C (EGCG 2.5mg/kg), D (EGCG 2.5mg/kg) + HAART) Brain histology, immunohistochemistry, and oxidative stress markers such as superoxide dismutase (SOD), glutathione (GSH),catalase (CAT)  and malondialdehyde (MDA) were examined. The use of highly active antiretroviral therapy (HAART) showed extensive architectural deformation with pyknotic neuronal cells and obliterated neurons in the hippocampus and prefrontal cortex. Expression of inflammasome cells was also evident in this group. MDA levels increased significantly with a significant reduction in the levels of GSH, as well as antioxidant enzyme (SOD and CAT) activities compared to other treatment groups. Treatment with EGCG resulted in partial neuronal restoration of histopathological alterations, and modulation of NLRP3 inflammasome in the hippocampus and prefrontal cortex. EGCG also showed significant improvements in terms of increased antioxidant levels of SOD, GSH, CAT and a reduced MDA level and well-preserved brain architecture. Epigallocatechin gallate improves brain morphology and function with a reversal of HAART-induced alterations.

Click to view file (PDF)



ADANA, M. Y., AKANG, E. N., NAIDU, E. C. S., ANIEKAN, P. I., KOUAME, K., OFFOR, U., OGEDENGBE, O. O. & AZU, O. O. 2018. Testicular microanatomical and hormonal alterations following use of antiretroviral therapy in Sprague Dawley rats: Role of Naringenin. Andrologia, 50, e13137.

AEBI, H. 1974. Catalase. Methods of enzymatic analysis. Elsevier.

AKANG, E. N., DOSUMU, O. O., AFOLAYAN, O. O., FAGOROYE, A. M., OSIAGWU, D. D., USMAN, I. T., OREMOSU, A. A. & AKANMU, A. S. 2019. Combination antiretroviral therapy (cART)-induced hippocampal disorders: highlights on therapeutic potential of Naringenin and Quercetin. IBRO reports, 6, 137-146.

ALBRO, P. W., CORBETT, J. T. & SCHROEDER, J. L. 1986. Application of the thiobarbiturate assay to the measurement of lipid peroxidation products in microsomes. Journal of Biochemical and Biophysical Methods, 13, 185-194.

ANGELOVA, P. R., ESTERAS, N. & ABRAMOV, A. Y. 2021. Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention. Medicinal Research Reviews, 41, 770-784.

ASSEFA, Y. & GILKS, C. F. 2020. Ending the epidemic of HIV/AIDS by 2030: Will there be an endgame to HIV, or an endemic HIV requiring an integrated health systems response in many countries? International Journal of Infectious Diseases, 100, 273-277.

BERTRAND, L., VELICHKOVSKA, M. & TOBOREK, M. 2021. Cerebral vascular toxicity of antiretroviral therapy. Journal of neuroimmune pharmacology, 16, 74-89.

CHANG, J. R., GHAFOURI, M., MUKERJEE, R., BAGASHEV, A., CHABRASHVILI, T. & SAWAYA, B. E. 2012. Role of p53 in neurodegenerative diseases. Neurodegenerative Diseases, 9, 68-80.

COBB, D. A., SMITH, N. A., EDAGWA, B. J. & MCMILLAN, J. M. 2020. Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research. Expert Opinion on Drug Delivery, 17, 1227-1238.

COUNCIL, N. 2010. Guide for the Care and Use of Laboratory Animals.[Google Scholar].

DAS, B. S., THURNHAM, D. I., PATNAIK, J. K., DAS, D. B., SATPATHY, R. & BOSE, T. K. 1990. Increased plasma lipid peroxidation in riboflavin-deficient, malaria-infected children. The American journal of clinical nutrition, 51, 859-863.

DOSUMU, O., AKANG, E., EDEM, E., AFOLAYAN, S. & AKANMU, A. 2021. Neurocognitive and Neuroarchitectural Changes in the Prefrontal Cortex of Wistar Rats Treated with Highly Active Antiretroviral Therapy. NIgerian Journal of Neuroscience, 12, 67-75.

EDAGHA, I. A., EKANEM, A. U., USOH, I. F., UMOH, V. A., ATABEN, A. M. & AKPAN, A. A. 2022. Brain antioxidants and hippocampal microanatomical alterations following the administration of Efavirenz/Lamivudine/Tenofovir disoproxil fumarate and Lamivudine/Nevirapine/Zidovudine in adult male Wistar rats. IBRO Neuroscience Reports, 12, 210-216.

EL KHOURY, A., SEIDLER, P. M., EISENBERG, D. S. & HARRAN, P. G. 2021. Catalytic Synthesis of PEGylated EGCG Conjugates that Disaggregate Alzheimer’s Tau. Synthesis, 53, 4263-4271.

EZE, G. & EKUNDINA, V. 2018. The effects of carbonated alcoholic herbal beverage on selected hepato-renal function indices, some haematological parameters and histopathology of adult male Wistar rats. Annals of Biomedical Sciences, 17.

FLESHNER, M., FRANK, M. & MAIER, S. F. 2017. Danger signals and inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology, 42, 36-45.

FORCANO, L., FAURIA, K., SOLDEVILA‐DOMENECH, N., MINGUILLÓN, C., LORENZO, T., CUENCA‐ROYO, A., MENEZES‐CABRAL, S., PIZARRO, N., BORONAT, A. & MOLINUEVO, J. L. 2021. Prevention of cognitive decline in subjective cognitive decline APOE ε4 carriers after EGCG and a multimodal intervention (PENSA): Study design. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 7, e12155.

FRIDOVICH, I. 1975. Superoxide dismutases. Annual review of biochemistry, 44, 147-159.

GARCIA, L., VAN DE WIJER, L., HANSWIJK, S., RANDO, J., WITTEVEEN, J., MIDDELMAN, A., TER HEINE, R., DE MAST, Q., MARTENS, G. & VAN DER VEN, A. 2020. Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture. Biochemical pharmacology, 178, 114050.

HE, J., XU, L. & LE YANG, X. W. 2018. Epigallocatechin gallate is the most effective catechin against antioxidant stress via hydrogen peroxide and radical scavenging activity. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 24, 8198.

HISER, J. & KOENIGS, M. 2018. The multifaceted role of the ventromedial prefrontal cortex in emotion, decision making, social cognition, and psychopathology. Biological psychiatry, 83, 638-647.

INOUE, Y., SHIRASUNA, K., KIMURA, H., USUI, F., KAWASHIMA, A., KARASAWA, T., TAGO, K., DEZAKI, K., NISHIMURA, S. & SAGARA, J. 2014. NLRP3 regulates neutrophil functions and contributes to hepatic ischemia–reperfusion injury independently of inflammasomes. The Journal of Immunology, 192, 4342-4351.

JAFARI, M., SALEHI, M., ASGARI, A., AHMADI, S., ABBASNEZHAD, M., HAJIHOOSANI, R. & HAJIGHOLAMALI, M. 2012. Effects of paraoxon on serum biochemical parameters and oxidative stress induction in various tissues of Wistar and Norway rats. Environmental toxicology and Pharmacology, 34, 876-887.

JAVED, H., AZIMULLAH, S., ABUL KHAIR, S. B., OJHA, S. & HAQUE, M. E. 2016. Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC neuroscience, 17, 1-12.

JENSEN, B. K., MONNERIE, H., MANNELL, M. V., GANNON, P. J., ESPINOZA, C. A., ERICKSON, M. A., BRUCE-KELLER, A. J., GELMAN, B. B., BRIAND, L. A. & PIERCE, R. C. 2015. Altered oligodendrocyte maturation and myelin maintenance: the role of antiretrovirals in HIV-associated neurocognitive disorders. Journal of Neuropathology & Experimental Neurology, 74, 1093-1118.

KEHINDE, S. O., OGEDENGBE, O. O., LINUS, E. A., ERINOMO, O. O., AJUMOBI, K. O., NAIDU, E. C. S. & AZU, O. O. 2021. Histomorphological study of the effects of aqueous extract of Curcuma longa on highly active antiretroviral therapy‐induced testicular toxicity. Andrologia, 53, e13952.

KIM, B.-H., KELSCHENBACH, J., BORJABAD, A., HADAS, E., HE, H., POTASH, M. J., NEDELCOVYCH, M. T., RAIS, R., HAUGHEY, N. J. & MCARTHUR, J. C. 2019. Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice. AIDS (London, England), 33, 973.

LAWAL, S. K., OLOJEDE, S. O., DARE, A., FABORODE, O. S., SULAIMAN, S. O., NAIDU, E. C., RENNIE, C. O. & AZU, O. O. 2022. Highly active antiretroviral therapy-silver nanoparticle conjugate interacts with neuronal and glial cells and alleviates anxiety-like behaviour in streptozotocin-induced diabetic rats. IBRO Neuroscience Reports.

LI, G., WANG, Y. & DE CLERCQ, E. 2021. Approved HIV reverse transcriptase inhibitors in the past decade. Acta Pharmaceutica Sinica B.

MAKHATHINI, K. B., MABANDLA, M. V. & DANIELS, W. M. 2018. Rosmarinic acid reverses the deleterious effects of repetitive stress and tat protein. Behavioural brain research, 353, 203-209.

MANDA, K. R., BANERJEE, A., BANKS, W. A. & ERCAL, N. 2011. Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood–brain barrier endothelial cells. Free Radical Biology and Medicine, 50, 801-810.

MATUSZEWSKA, A., NOWAK, B., NIŻAŃSKI, W., EBERHARDT, M., DOMRAZEK, K., NIKODEM, A., WIATRAK, B., ZDUNIAK, K., OLEJNIK, K. & MERWID-LĄD, A. 2021. Long-Term Administration of Abacavir and Etravirine Impairs Semen Quality and Alters Redox System and Bone Metabolism in Growing Male Wistar Rats. Oxidative Medicine and Cellular Longevity, 2021.

MORALES, M. & MUNNÉ-BOSCH, S. 2019. Malondialdehyde: facts and artifacts. Plant physiology, 180, 1246-1250.

NAIR, H. H., ALEX, V. V. & ANTO, R. J. 2021. Significance of nutraceuticals in cancer therapy. Evolutionary Diversity as a Source for Anticancer Molecules. Elsevier.

OGEDENGBE, O., NAIDU, E., AKANG, E., OFFOR, U., ONANUGA, I., PETER, A., JEGEDE, A. & AZU, O. 2018a. Virgin coconut oil extract mitigates testicular‐induced toxicity of alcohol use in antiretroviral therapy. Andrology, 6, 616-626.

OGEDENGBE, O. O., JEGEDE, A. I., ONANUGA, I. O., OFFOR, U., NAIDU, E. C., PETER, A. I. & AZU, O. O. 2016. Coconut oil extract mitigates testicular injury following adjuvant treatment with antiretroviral drugs. Toxicological research, 32, 317-325.

OGEDENGBE, O. O., NAIDU, E. & AZU, O. O. 2018b. Antiretroviral therapy and alcohol interactions: X-raying testicular and seminal parameters under the HAART era. European journal of drug metabolism and pharmacokinetics, 43, 121-135.

PASTERNAK, A. O., VROOM, J., KOOTSTRA, N. A., WIT, F. W., DE BRUIN, M., DE FRANCESCO, D., BAKKER, M., SABIN, C. A., WINSTON, A. & PRINS, J. M. 2021. Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors. medRxiv.

PERDICES, L., FUENTES-BROTO, L., SEGURA, F., CUENCA, N. & PINILLA, I. 2020. Epigallocatechin gallate slows retinal degeneration, reduces oxidative damage, and modifies circadian rhythms in P23H rats. Antioxidants, 9, 718.

PONGBULAAN, A. & TRIYONO, E. A. 2021. Gigantomastia Bilateral Induced Efavirenz: A Case Report. Indian Journal of Forensic Medicine & Toxicology, 15.

PRATS, A., MARTÍNEZ-ZALACAÍN, I., MOTHE, B., NEGREDO, E., PÉREZ-ÁLVAREZ, N., GAROLERA, M., DOMÈNECH-PUIGCERVER, S., COLL, P., MEULBROEK, M. & CHAMORRO, A. 2021. Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection. Scientific reports, 11, 1-9.

PRIYA, L. B., BASKARAN, R. & PADMA, V. V. 2017. Phytonanoconjugates in oral medicine. Nanostructures for Oral Medicine. Elsevier.

REZNICHENKO, L., KALFON, L., AMIT, T., YOUDIM, M. B. & MANDEL, S. A. 2010. Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism. Neurodegenerative Diseases, 7, 219-231.

RU, W. & TANG, S.-J. 2017. HIV-associated synaptic degeneration. Molecular brain, 10, 1-13.

SAEIDNIA, S. & ABDOLLAHI, M. 2014. Role of micronutrients and natural antioxidants in fighting against HIV; a quick mini-review. Research Journal of Pharmacognosy, 1, 49-55.

SANFORD, R., FELLOWS, L. K., ANCES, B. M. & COLLINS, D. L. 2018. Association of brain structure changes and cognitive function with combination antiretroviral therapy in HIV-positive individuals. JAMA neurology, 75, 72-79.

SEBASTIANI, G., ALMEIDA-TOLEDANO, L., SERRA-DELGADO, M., NAVARRO-TAPIA, E., SAILER, S., VALVERDE, O., GARCIA-ALGAR, O. & ANDREU-FERNÁNDEZ, V. 2021. Therapeutic effects of catechins in less common neurological and neurodegenerative disorders. Nutrients, 13, 2232.

SEDLAK, J. & LINDSAY, R. H. 1968. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Analytical biochemistry, 25, 192-205.

SHUKLA, R., PANDEY, V., VADNERE, G. P. & LODHI, S. 2019. Role of flavonoids in management of inflammatory disorders. Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases. Elsevier.

SIGURDSSON, T. & DUVARCI, S. 2016. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Frontiers in systems neuroscience, 9, 190.

SINGH, N. A., MANDAL, A. K. A. & KHAN, Z. A. 2015. Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG). Nutrition journal, 15, 1-17.

STERN, J., SOLOMON, A., DANTANARAYANA, A., PASCOE, R., REYNALDI, A., DAVENPORT, M. P., MILUSH, J., DEEKS, S. G., HARTOGENSIS, W. & HECHT, F. M. 2021. Cell-associated HIV RNA has a Circadian Cycle in Males Living with HIV on Antiretroviral Therapy. The Journal of Infectious Diseases.

STRECK, E. L., SCAINI, G., REZIN, G. T., MOREIRA, J., FOCHESATO, C. M. & ROMÃO, P. R. 2008. Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity. Metabolic brain disease, 23, 485-492.

TIAN, M., CHEN, G., XU, J., LIN, Y., YI, Z., CHEN, X., LI, X. & CHEN, S. 2022. Epigallocatechin gallate-based nanoparticles with reactive oxygen species scavenging property for effective chronic periodontitis treatment. Chemical Engineering Journal, 433, 132197.

VELICHKOVSKA, M., SURNAR, B., NAIR, M., DHAR, S. & TOBOREK, M. 2018. Targeted mitochondrial COQ10 delivery attenuates antiretroviral-drug-induced senescence of neural progenitor cells. Molecular pharmaceutics, 16, 724-736.

XU, Y.-Q., GAO, Y. & GRANATO, D. 2021. Effects of epigallocatechin gallate, epigallocatechin and epicatechin gallate on the chemical and cell-based antioxidant activity, sensory properties, and cytotoxicity of a catechin-free model beverage. Food chemistry, 339, 128060.

XUE, Y., DU, H.-D., TANG, D., ZHANG, D., ZHOU, J., ZHAI, C.-W., YUAN, C.-C., HSUEH, C.-Y., LI, S.-J. & HENG, Y. 2019. Correlation between the NLRP3 inflammasome and the prognosis of patients with LSCC. Frontiers in oncology, 9, 588.

YANG, Y., LIU, X., WU, T., ZHANG, W., SHU, J., HE, Y. & TANG, S.-J. 2018. Quercetin attenuates AZT-induced neuroinflammation in the CNS. Scientific reports, 8, 1-8.

ZHANG, F., MA, Y., ZHAO, Y. & DONG, W. 2020. Strategy to achieve full coverage in the national free antiretroviral therapy program. HIV/AIDS in China. Springer.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Copyright (c) 2023 Nigerian Journal of Physiological Sciences