Therapeutic activities of naringenin on efavirenz-induced sleep-like disorder in the midbrain of white albino mice

Document Type: Original Article

Authors

1 Department of Anatomy, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria

2 Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria

10.22038/ijbms.2020.47043.10852

Abstract

Objective(s): Efavirenz, has proven to be effective in suppressing human immunodeficiency virus (HIV) viral load; however, complaints of sleep disorders including hallucination, and insomnia have greatly contributed to non-adherence to antiretroviral therapy. This study aimed at investigating therapeutic activities of naringenin on efavirenz-induced sleep disorder.
Materials and Methods: Sixty mice were divided into six groups of control, combination antiretroviral therapy (cART), efavirenz, naringenin, naringenin/efavirenz and naringenin/cART. Efavirenz, cART, and naringenin were administered orally and daily at 15 mg/kg, 24 mg/kg and 50 mg/kg, respectively for 28 days. Post neurobehavioral test, oxidative stress, histology and immunohistochemistry for dopamine were carried out after administration process.
Results: Efavirenz (p <0.0001) and cART (p <0.01) significantly increased immobility during open field (p <0.01), escape time in seconds (sec) in Morris water maze (p <0.001) and numbers of head-twitch response (HTR) (p <0.0001). Similarly, there was a significant increase in malondialdehyde (MDA) (p <0.0001) and decreased superoxide dismutase (SOD) (p <0.001) and reduced glutathione (GSH) (p <0.001); however, naringenin-treated groups potentiated anti-oxidant function by reducing oxidative stress (p <0.01). Histological evaluation demonstrated severe neurodegeneration, vacuolization and pyknosis in efavirenz and cART compared to naringenin groups. Dopaminergic neurons using immunohistochemial antibody (tyrosine hydroxylase) staining showed poor immunoreactivity in efavirenz and cART in contrast to naringenin groups.
Conclusion: Efavirenz and cART have the potential of inducing sleep disorder possibly due to their capability to trigger inflammation and deplete dopamine level. However, naringenin has proven to be effective in ameliorating these damages.

Keywords


1. UNAIDS. Fact sheet: latest statistics on the status of the AIDS epidemic. 2018.
2. Assefa Y, Gilks CF. Second-line antiretroviral therapy: so much to be done. Lancet  2017; 4:424-425.
3. Stubbs M. Update on antiretrovirals. South Afr J Anaesth Analg 2018; 24:25-30.
4. WHO. Global health sector strategy on HIV/AIDS 2016-2021. 2018.
5. Granich R, Gupta S, Wollmers M, Ruffner M, Williams B. Modeling the HIV Epidemic: Why the 95-95-95 Target and ART Effectiveness Parameters Matter. Int J Virol AIDS 2018; 5:1-9.
6. Martínez-Salazar MF, Oaxaca-Navarro J, Leija-Salas A, García-Jiménez S, Sánchez-Alemán MA, Déciga-Campos M. Analysis of self-reported adverse reactions to efavirenz and drug interactions in a population with HIV in Mexico. Eur J Hosp Pharm 2018; 25:322-326.
7. Oshinaike O, Akinbami A, Ojelabi O, Dada A, Dosunmu A, John Olabode S. Quality of sleep in an HIV population on antiretroviral therapy at an urban tertiary centre in Lagos, Nigeria. Neurol res int 2014; 2014:298703-298709.
8. Mueller TE, Ellwanger JH, Michita RT, Matte MCC, Renner JD. CYP2B6 516 G> T polymorphism and side effects of the central nervous system in HIV-positive individuals under Efavirenz treatment: Study of a sample from southern Brazil. An Acad Bras Cienc 2017; 89:497-504.
9. Apostolova N, Funes HA, Blas-Garcia A, Galindo MJ, Alvarez A, Esplugues JV. Efavirenz and the CNS: what we already know and questions that need to be answered. J Antimicrob Chemother 2015; 70:2693-2708.
10. Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, et al. The HIV antiretroviral drug efavirenz has LSD-like properties. Neuropsychopharmacology 2013; 38:2373-2384.
11. Cavalcante GI, Chaves Filho AJM, Linhares MI, de Carvalho Lima CN, Venâncio ET, Rios ER, et al. HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum. Eur J pharmacol 2017; 799:7-15.
12. Adana MY, Akang E, Peter A, Jegede A, Naidu E, Tiloke C, et al. Naringenin attenuates highly active antiretroviral therapy-induced sperm DNA fragmentations and testicular toxicity in Sprague-Dawley rats. Andrology 2018; 6:166-175.
13. Corne S, Pickering R, Warner B. A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine. Br j Pharmacol Chemother 1963; 20:106-120.
14. Akang EN, Dosumu OO, Afolayan OO, Fagoroye AM, Osiagwu DD, Usman IT, et al. Combination antiretroviral therapy (cART)-induced hippocampal disorders: Highlights on therapeutic potential of Naringenin and Quercetin. IBRO reports 2019; 6:137-146.
15. Dalwadi DA, Ozuna L, Harvey BH, Viljoen M, Schetz JA. Adverse neuropsychiatric events and recreational use of efavirenz and other HIV-1 antiretroviral drugs. Pharmacol Rev 2018; 70:684-711.
16. Akang EN, Adana MY, Peter AI, Naidu EC, Mackraj I, Azu OO. Testicular 3beta hydroxysteroid dehydrogenase in naringenin adjuvant under highly active antiretroviral therapy (HAART): preliminary data using Sprague-Dawley rats. Europ J Anat 2019; 23:1-7.

17. Akang E, Dosumu O, Afolayan S, Agumah R, Akanmu AS. Modeling cerebellar limb dysmetria and impaired spatial memory in rats using lamivudine: a preliminary study. J Chem Neuroanat 2020; 109: 101838-101848.
18. Oremosu AA, Akang EN, Dosumu OO, Usman IT, Akanmu AS. Cerebellar perturbations of combination antiretroviral therapy (cART): can bioflavonoids help? Nigerian J Neurosci 2018; 9:53-59.
19. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1:848-458.
20. Kuo WY, Huang CH, Shih C, Jinn TL. Cellular extract preparation for superoxide dismutase (SOD) activity assay. Bio protoc 2013; 3:811-815.
21. Reiner K. Catalase test protocol. ASM MicrobeLibrary 2010; 11:1-9.
22. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82:70-77.
23. Tsikas D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal  Biochem 2017; 524:13-30.
24. Fischer AH, Jacobson KA, Rose J, Zeller R. Hematoxylin and eosin staining of tissue and cell sections. Cold Spring Harb Protoc 2008; 2008:1-3.
25. Wang GQ, Zhang B, He XM, Li DD, Shi JS, Zhang F. Naringenin targets on astroglial Nrf2 to support dopaminergic neurons. Pharmacol Res 2019; 139:452-459.
26. Cavalcante G, Capistrano V, Cavalcante F, Vasconcelos S, Macedo D, Sousa F, et al. Implications of efavirenz for neuropsychiatry: a review. Int J Neurosci 2010; 120:739-745.
27. Ngaimisi E, Mugusi S, Minzi O, Sasi P, Riedel KD, Suda A, et al. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharmacol Ther 2010; 88:676-684.
28. Waters L, Fisher M, Winston A, Higgs C, Hadley W, Garvey L, et al. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine AIDS 2011; 25:65-71.
29. Gaida R, Truter I, Grobler C, Kotze T, Godman B. A review of trials investigating efavirenz-induced neuropsychiatric side effects and the implications. Expert Rev Anti Infect Ther 2016; 14:377-388.
30. Gazzard B, Balkin A, Hill A. Analysis of neuropsychiatric adverse events during clinical trials of efavirenz in antiretroviral-naive patients: a systematic review. AIDS Rev 2010; 12:67-75.
31. Nelson M, Elion R, Cohen C, Mills A, Hodder S, Segal-Maurer S, et al. Rilpivirine versus efavirenz in HIV-1–infected subjects receiving emtricitabine/tenofovir DF: Pooled 96-week data from ECHO and THRIVE studies. HIV Clin Trials 2013; 14:81-91.
32. Costa M, Abreu M, Rêgo N. Factors of nonadherence to antiretroviral treatment in Amapá, Brazil. Int J Infect Dis 2018; 73:242-243.
33. Habtewold A, Amogne W, Makonnen E, Yimer G, Nylen H, Riedel K, et al. Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients. Pharmacogenomics J 2013; 13:484-489.
34. Jiang F, Desta Z, Shon JH, Yeo CW, Kim HS, Liu KH, et al. Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index. Br J Clin Pharmacol 2013; 75:244-253.
35. Yi LT, Li CF, Zhan X, Cui CC, Xiao F, Zhou LP, et al. Involvement of monoaminergic system in the antidepressant-like effect of the flavonoid naringenin in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 2010; 34:1223-1228.
36. Alzoubi KH, Malkawi BS, Khabour OF, El-Elimat T, Alali FQ. Arbutus andrachne L. reverses sleep deprivation-induced memory impairments in rats. Mol Neurobiol 2018; 55:1150-1156.
37. Havekes R, Bruinenberg VM, Tudor JC, Ferri SL, Baumann A, Meerlo P, et al. Transiently increasing cAMP levels selectively in hippocampal excitatory neurons during sleep deprivation prevents memory deficits caused by sleep loss. J Neurosci 2014; 34:15715-15721.
38. Tryon VL, Mizumori SJ. A novel role for the periaqueductal gray in consummatory behavior. Front Behav Neurosci 2018; 12:178-193.
39. Cellini N. Memory consolidation in sleep disorders. Sleep Med Rev 2017; 35:101-112.
40. Opii WO, Sultana R, Abdul HM, Ansari MA, Nath A, Butterfield DA. Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′, 3′-dideoxycytidine (ddC): relevance to HIV-dementia. Exp Neurol 2007; 204:29-38.
41. Gaida R, Truter I, Grobler C. Efavirenz: A review of the epidemiology, severity and management of neuropsychiatric side-effects. S Afr J Psychi 2015; 21:94-97.
42. Manchope MF, Calixto-Campos C, Coelho-Silva L, Zarpelon AC, Pinho-Ribeiro FA, Georgetti SR, et al. Naringenin inhibits superoxide anion-induced inflammatory pain: role of oxidative stress, cytokines, Nrf-2 and the NO− cGMP− PKG− KATPChannel signaling pathway. PloS One 2016; 11:153015-153035.
43. Bulboaca AE, Bolboaca SS, Stanescu IC, Sfrangeu CA, Bulboaca AC. Antioxidant effect of flavonoids in neurodegenerative disease. Rom J Neurol 2017; 16:46-52.
44. Al-Dosari DI, Ahmed MM, Al-Rejaie SS, Alhomida AS, Ola MS. Flavonoid naringenin attenuates oxidative stress, apoptosis and improves neurotrophic effects in the diabetic rat retina. Nutrients 2017; 9:1161-1174.
45. Adjene JO, Avbunudiogba JA, Awhin PE, Igbigbi PS. Biochemical effects of chronic administration of efavirenz on the intracranial auditory relay centers of adult Wistar rats. Genomic Med Biomark Health Sci 2012; 4:85-89.
46. Shakeel S, Rehman MU, Tabassum N, Amin U. Effect of naringenin (a naturally occurring flavanone) against pilocarpine-induced status epilepticus and oxidative stress in mice. Pharmacogn Mag 2017; 13:154-160.
47. Barres BA. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 2008; 60:430-440.
48. Kang W, Balordi F, Su N, Chen L, Fishell G, Hébert JM. Astrocyte activation is suppressed in both normal and injured brain by FGF signaling. Proc Natl Acad Sci U S A 2014; 111:2987-2995.
49. de Sampaio e Spohr TCL, Stipursky J, Sasaki AC, Barbosa PR, Martins V, Benjamim CF, et al. Effects of the flavonoid casticin from Brazilian Croton betulaster in cerebral cortical progenitors in vitro: Direct and indirect action through astrocytes. J Neurosci Res 2010; 88:530-541.
50. de Pablo Y, Nilsson M, Pekna M, Pekny M. Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen–glucose deprivation and reperfusion. Histochem Cell Biol 2013; 140:81-91.
51. Schiweck J, Eickholt BJ, Murk K. Important shapeshifter: mechanisms allowing astrocytes to respond to the changing nervous system during development, injury and disease. Front Cell Neurosci 2018; 12:261-278.
52. Chamberlain SR, Grant JE. Behavioral Addictions. A Transdiagnostic Approach to Obsessions, Compulsions and Related Phenomena. 2019:401.
53. Claassen DO, Stark AJ, Spears CA, Petersen KJ, van Wouwe NC, Kessler RM, et al. Mesocorticolimbic hemodynamic response in Parkinson’s disease patients with compulsive behaviors. Mov Disord 2017; 32:1574-1583.
54. Lim MM, Xu J, Holtzman DM, Mach RH. Sleep deprivation differentially affects dopamine receptor subtypes in mouse striatum. Neuroreport 2011; 22:489-493.
55. Mamelak M. Parkinson’s disease, the dopaminergic neuron and gammahydroxybutyrate. Neurol Ther 2018; 7:5-11.
56. Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic Res 2005; 39:1119-11125.
57. Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X. Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology 2014; 79:380-388.