High-dose subacute and acute thymoquinone treatments alleviate LPS-induced depressive-like behavior in mice by reducing inflammation via the IDO/KYN pathway

Abstract

The present study aimed to evaluate the antidepressant-like activity of thymoquinone (TQ) in lipopolysaccharide (LPS)-induced depressive-like behavior by inhibiting indoleamine 2,3 dioxygenase (IDO). IDO degrades tryptophan (TRP) along the kynurenine (KYN) pathway. TQ, the main bioactive compound found in black seed (Nigella sativa) oil, possesses numerous biological activities, including anti-oxidants and anti-inflammation properties. Subacute and acute TQ treatments were administered to mice at doses of 5 and 20 mg/kg. Depression-like behavior was assessed using the forced swim test (FST), Tail Suspension Test (TST), Open Field Test (OFT), and Sucrose Preference test (SPT). Blood flow following LPS and TQ administration was explored using laser speckle imaging, while a transmission electron microscope was used to investigate ultrastructural changes in the hippocampus. The mechanism of action was further explored by measuring protein expression levels and performing qPCR. Subacute and acute TQ treatments at dose 20 mg/kg significantly reduced immobility periods in stressed mice indicating robust antidepressant-like activity under stress conditions. Acute TQ 5 mg/kg treatment showed non significant effect on locomotor activity, whereas, subacute TQ 5 mg/kg treatment exhibited slight improvements in behavioral tests and modest downregulation of apoptosis and inflammatory proteins. TQ treatment also improved blood flow following LPS-induced depression, significantly reduced IDO/KYN expression levels, and increased TRP and 5-HT levels. Additionally, TQ protected neurons, axons, and synapses after LPS injection. These finding suggest that TQ exerts significant antidepressant-like activity in mice, potentially through its anti-inflammatory effects and inhibition of IDO activity.