Potential Mechanisms of Imidacloprid-Induced Neurotoxicity in Adult Rats with Attempts on Protection Using Origanum majorana L. Oil/Extract: In Vivo and In Silico Studies

Imidacloprid (IMI) insecticide is rapidly metabolizedin mammalsand contributes to neurotoxicity via the blocking of nicotinic acetylcholinereceptors, as in insects. Origanum majorana retains its great antioxidant potential in both fresh and dry forms.No data is available on the neuroprotective effect of this plant inlaboratory animals. In this context, aerial parts of O. majorana were used to prepare the essential oil(OMO) and methanol extract (OME). The potential neuroprotective impactof both OMO and OME against IMI-induced neurotoxicity in rats wasexplored. Forty-two rats were divided into 6 groups, with 7 rats ineach one. Rats were daily administered the oral treatments: normalsaline, OMO, OME, IMI, IMI + OMO, and IMI + OME. Our results revealedthe identification of 55 components in O. majorana essential oil, most belonging to the oxygenated and hydrocarbonmonoterpenoid group. Moreover, 37 constituents were identified inthe methanol extract, mostly phenolics. The potent neurotoxic effectof IMI on rats was confirmed by neurobehavioral and neuropathologicalalterations and a reduction of both acetylcholine esterase (AchE)activity and dopamine (DA), serotonin (5HT), and gamma-aminobutyricacid (GABA) levels in the brain. Exposure of rats to IMI elevatesthe malondialdehyde (MDA) levels and reduces the antioxidant capacity.IMI could upregulate the transcription levels of nuclear factor-kappa B(NF-kappa B), interleukin-1 beta (IL-1 beta), and tumor necrosisfactor (TNF-alpha) genes and express strong caspase-3 and induciblenitric oxide synthase (iNOS) immunostaining in most examined brainareas. On the other hand, rats coadministered OMO or OME with IMIshowed a marked improvement in all of the studied toxicological parameters.In conclusion, cotreatment of O. majorana extracts with IMI can protect against IMI neurotoxicity via theirpotent antioxidant, anti-inflammatory, and anti-apoptotic effects.Thus, we recommend a daily intake of O. majorana to protect against insecticide's oxidative stress-mediatedneuroinflammatory stress and apoptosis. The molecular docking studyof linalool, rosmarinic acid, gamma-terpene, and terpene-4-ol justifythe observed normalization of the elevated iNOS and TNF-alpha levelsinduced after exposure to IMI.