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

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. 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. 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. 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.