Aqueous and Ethanol Extracts of Acacia sieberiana (Fabaceae) Stem Bark Reverse the Pain–Depression Dyad in Mice Through Modulation of Catecholamines, Proinflammatory Cytokines, and Oxidative Stress

Rationale and Objective: The pain–depression dyad is highly prevalent and has reciprocal psychological and behavioral effects, leading to poor quality of life, increased disability, and challenging therapeutic outcomes. In an attempt to find better substances that can target pain–depression comorbidity, we examined the effect of aqueous (AE) and ethanol (EE) extracts from Acacia sieberiana (A. sieberiana) stem bark on reserpinized mice (female and male Swiss albino mice aged 2-3 months). Methods: The dyad was induced with 3 injections (Days 1–3) of reserpine (1 mg/kg/day, s.c.). Then, animals were treated (Days 4–8) with plant extracts (25, 50 and 100 mg/kg/day, p.o.) or L-tryptophane (100 mg/kg/day, i.p.). Pain-like (tactile and cold allodynia) and depression-like (pole, tail suspension, and force swimming tests) behavioral parameters were evaluated on Days 4 and 8. On Day 9, animals were sacrificed for the quantification of acetylcholinesterase activity, oxidative stress parameters, total catecholamines, dopamine, serotonin, IL-1β, and TNF-α levels in the brain or spinal cord. IL-1β and TNF-α were also assayed in the serum. The acute toxicity and phytochemical analysis of EE were conducted. Results: Reserpine-induced tactile and cold allodynia, depression-like behavior, increased serum IL-1β and TNF-α, brain acetylcholinesterase activity, and decreased catecholamine concentration were all reversed by AE and EE. Plant extracts significantly increased dopamine levels and reduced oxidative stress in the brain and/or spinal cord. No significant effect was observed on brain serotonin and TNF-α. EE elicited the best pharmacological activity and was nontoxic. LC–MS/MS molecular networking phytochemical analysis identified 5 compounds with high certainty including piperine, aurantiamide acetate, and asperphenamate. Conclusion: AE and EE are effective against pain and depression. Their pharmacological activities might be related to the modulation of inflammation, oxidative stress and catecholamine, and the presence of bioactive natural products.