Ferulic Acid Modulates Dysfunctional Metabolic Pathways and Purinergic Activities, While Stalling Redox Imbalance and Cholinergic Activities in Oxidative Brain Injury

The neuroprotective activities of phenolics have been demonstrated in several studies, with their antioxidant properties playing an influential role. In this study, the therapeutic effect of ferulic acid was investigated on oxidative stress, purinergic and cholinergic enzymatic activities, and dysregulated metabolic pathways in oxidative brain injury. Ferulic acid significantly elevated the reduced glutathione (GSH) level, superoxide dismutase and catalase activities, and concomitantly depleted malondialdehyde and nitric oxide level. It also inhibited the activities of acetylcholinesterase and butyrylcholinesterase, and increased the activities of ATPase. LC-MS analysis of the metabolites revealed restoration of most depleted metabolites, with concomitant generation of dihydroferulic acid 4-O-glucuronide, diadenosine heptaphosphate, cis-4-decenoic acid, ganglioside GT3 (d18:0/23:0), phosphatidylinositol-3,4,5-trisphosphate, and phosphoribosyl-ATP on treatment with ferulic acid. Pathway analysis of the identified metabolites revealed reactivation of oxidative-inactivated pathways, with concomitant activation of histidine and inositol phosphate metabolic pathways. There was no cytotoxicity on incubation of ferulic acid with HT22 cells. Molecular docking studies revealed a high affinity for acetylcholinesterase, with a binding energy of - 7.4 kcal/mol. In silico simulation analysis predicted permeability of ferulic acid across blood brain barrier (BBB) and an oral LD₅₀ calculated value of 1772 mg/kg, with a toxicity class of 4. These results indicate the antioxidative and protective effects of ferulic acid in oxidative brain injury.