High Dietary Fat Modulates Neurobehavioural Effect of Lopinavir/ Ritonavir in Mice

Abstract

Background: Lopinavir/Ritonavir (LR) is a protease inhibitor used human immunodeficiency virus infection management. There have been issues regarding the effects of fat on LR efficacy and the possibility of neurological deficits following prolonged use, there is however a dearth of research examining this. Aims: The effects of LR administered with normal or High-Fat Diet (HFD) on neurobehaviour, neurochemistry and oxidative stress in healthy mice were examined. Methods: Mice were randomly-assigned into eight groups of ten (n=10) animals each. The groups were normal control [Standard Diet, (SD)], HFD control, 3 groups of LR incorporated into SD (100/25, 200/50 and 400/100 mg/kg of feed), and 3 groups of LR with HFD (100/25, 200/50 and 400/100 mg/kg of feed). Mice were fed daily for six weeks, following which open field, elevated-plus maze (EPM), radial-arm maze and Y-maze behaviours were scored. Twenty-four hours after tests, mice were euthanised and brains were homogenised for estimation of oxidative stress, L-glutamate level and acetylcholinesterase activity. Results: LR was associated with a reduction in HFD-induced weight gain, suppression of open-field behaviours with SD, and counteraction of HFD-induced changes in working-memory, open-field and anxiety-related behaviours. Also, LR causes increased lipid peroxidation and superoxide dismutase activity; and a decrease in brain glutamate, irrespective of dietary composition. Increased fat catabolism leading to increased oxidative stress could possibly account for the weight changes, while a decrease in brain glutamate could account for the changes in open-field behaviours in mice fed SD. Conclusion: LR alters neurobehaviour, oxidative stress and brain glutamate in mice; however, only its effects on neurobehaviour are affected by diet.

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“…Each arm radiates from a small circular central platform.. Each rat is placed on the central platform of the maze and allowed to move freely through respective arms while its behaviours were recorded for 5 min. Working memory was scored when the rat entered each arm a single time as described previously [30, 31]. .…”

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“…An alternation is defined as consecutive entry into all three arms. The percentage alternation was calculated from the number of sequential arm entries into the three arms (actual alternation arm entry) divided by the total arm entry after a factor of two has been subtracted from it as previously described (17,18).…”

“…Re-entry into the arms is scored as a working memory error. Spatial working memory was assessed as alternation index, which is defined as the ratio of sequential arm entries before error as previously described (17,18).…”

“…Colour changes were measured at an absorbance of 560 nm as described previously (22). Nitric oxide assay was carried out using the Nitric oxide kit as previously described (17). The change in absorbance at 540 nm over 5 minutes was measured.…”

“…Level of dopamine in the homogenate was assayed using commercially-available dopamine assay kit following the instructions of the manufacturer and as previously described (17,23). Color change was measured at an absorbance of 450 nm as specified by the manufacturer.…”