Neuroprotective Potential of Jimson Weed in Methotrexate-Induced Neurotoxicity: Insights into Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Mechanisms via Modulation of Caspase-3, Interleukin-6, and Tumor Necrosis Factor-Alpha: In Silico

Abstract

OBJECTIVE: Methotrexate (MTX) is a drug of choice for the treatment of different types of cancers and autoimmune disorders. Despite its effectiveness, its toxicity is the major drawback of its use. It is a chemotherapy drug known to cause neurotoxicity, leading to oxidative stress, inflammation, and apoptosis in the brain. We evaluated the outcome of ethanol leaf extract of Jimson weed (ELEJW) on neurotoxicity prompted by MXT use. METHODS: Forty albino rats (male) were assigned into four categories (n=10): 1=Control (5 mg/kg normal saline); 2= Extract (200 mg/kg ELEJW); 3= MXT (20 mg/kg MXT); 4= Test (200 mg/kg ELEJW + 20 mg/kg MXT). MXT was given on day 18 only (ip) while ELEJW was by gavage for 21 days. Identified compounds from the plant were docked against caspase-3, interleukin-6, and tumor necrosis factor-alpha(tnf-α), while the drug-likeness properties were investigated in silico using ADNETSAR and Swiss adme web servers. RESULTS: MXT injection caused oxidative stress, inflammation, and increased cerebral cell death in rats as evidenced by elevation in SOD, CAT, GPx, AchE, and Caspase-3 activities and also increases in MDA, NO, IL-6, and TNF- α concentrations. Intriguingly, ELEJW administration to rats reversed this trend. Jimson weed showed a significant reduction in these neurotoxic effects. Jimson weed treatment led to a decrease in oxidative stress markers, a reduction in inflammatory cytokines, and a decrease in apoptotic markers in the brain tissue of methotrexate-treated rats via modulation of caspase-3, interleukin-6, and tumor necrosis factor-alpha(tnf-α). The histological alterations caused by MXT were resolved as intact neuronal cells with normal glial and pyramidal cells were observed. In silico analysis identified two compounds 1H-Indole and 2,3-Dimethylquinolin- 4(1H)-one from ELEJW with potentially strong binding affinities towards caspase-3, interleukin- 6, and tumor necrosis factor-alpha(tnf-α) via molecular docking and expression of stable hydrogen, pi, sigma, and Van der Waals' interactions between target proteins, and screened ligands, while the drug-likeness properties of these compounds show no significant violation of Lipinski, Ghose, and Verber rules. CONCLUSIONS: Co-treatment of ELEJW with MXT overturned the oxidative stress, inflammation, and histological alterations perpetuated by MXT. Therefore, Jimson weed should be explored as a supportive therapy for the management of MXT-induced neurological derangements.