Cannabidiol-rich Cannabis sativa L. Extract Alleviates LPS-Induced Neuroinflammation in Male Mice: Computational Inference with Deep Learning Approach

Abstract

Neuroinflammation is a hallmark of various neurodegenerative disorders, yet effective treatments remain limited. This study investigates the neuroprotective potential of a Cannabis sativa L. (C.S) extract rich in cannabidiol (CBD) and containing THC, CBG, THCV, and β-caryophyllene in a lipopolysaccharide (LPS)-induced neuroinflammation Male mice model. The effects on anxiety-like behavior, cognitive function, and locomotor activity were assessed using behavioral tests (open field, elevated plus maze, novel object recognition, and Morris water maze). Antioxidant activity was measured by assaying glutathione (GSH) levels and lipid peroxidation by-products (TBARs). Anti-inflammatory properties were evaluated using quantitative reverse transcription polymerase chain reaction (QRt-PCR) for proinflammatory cytokines (IL-6 and TNF-α), glial fibrillary acidic protein (GFAP), and cannabinoid receptor 1 (CB1) mRNAs in the prefrontal cortex (PFC). Additionally, the metabolic activity of cortical astrocytes was assessed. Compared to synthetic CBD, the C.S extract (20.0 mg/kg) demonstrated superior efficacy in attenuating LPS-induced anxiety-like behavior, cognitive decline, and locomotor impairments. It also significantly mitigated oxidative stress (increased GSH, reduced TBARs) and suppressed pro-inflammatory cytokines and GFAP mRNAs, indicating potent anti-inflammatory properties. The extract modulated CB1 receptor expression and preserved metabolic homeostasis in cortical astrocytes, preventing their shift from glycolysis to oxidative phosphorylation under neuroinflammatory conditions. Deep learning approaches revealed that Delta-9-THC’s conformational change at residues Phe200 and Trp356 in the CB1 receptor synergistically enhances CBD’s effect. These findings highlight the therapeutic potential of C.S extract for managing neuroinflammatory disorders, warranting further investigation into its clinical applications and underlying mechanisms