Zanthoxylum alatum attenuates lipopolysaccharide-induced depressive-like behavior in mice hippocampus

Background: Zanthoxylum alatum (ZA) is used ethnomedicinally for the treatment of various diseases. It is used as a nerve tonic in weak patients and in vertigo. Objective: The beneficial effect of hydroethanolic extract of ZA seeds (HEZA) on lipopolysaccharide (LPS)-induced depression-like behavior in mice was studied with its possible underlying mechanisms. Materials and Methods: HEZA (100 and 200 mg/kg, p.o.) and imipramine (10 mg/kg, i.p) were administered for 14 consecutive days, followed by LPS (0.83 mg/kg i.p) injection, 30 min posttreatment. Behavioral studies including the open field test, forced swimming test, tail suspension test and sucrose preference test were performed after 24 h of LPS administration. Levels of pro-oxidant markers (Lipid peroxidation (LPO), Nitric oxide (NO) and antioxidant enzyme viz. Glutathione (GSH), Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx) were estimated biochemically; Norepinephrine (NE), Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels by high-performance liquid chromatography; nuclear factor- κB (NFκB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and caspase-3 mRNA expression using reverse transcription-polymerase chain reaction; the proteins of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB), in hippocampal tissue were evaluated by Western blot. Hesperidin, magnoflorine, melicopine, and sesamin were few phytoconstituents identified by liquid chromatography–electrospray ionization–tandem mass spectrometry studies. Results: Administration of LPS produced significant depression-like behavior by reducing the locomotor activity in open field test, increasing the immobility time in forced swim test and tail suspension test, increased LPO, NO, decreased GSH, SOD, CAT, GPx levels; lowered NE, DA and 5-HT level, upregulated NFκB, Nrf2 and Caspase-3 mRNA expression and downregulated BDNF, TrKB protein expression. Pretreatment with imipramine and HEZA reversed LPS-induced behavioral patterns, inhibited oxido-nitrosative stress, elevated antioxidant enzyme levels, and normalized the NE, DA, and 5-HT levels. The treatment also suppressed the mRNA expression of NFκB, Nrf2, and Caspase-3 gene with upregulation of BDNF protein expression, the molecular marker for depression. Conclusion: Antidepressant-like activity of HEZA is assumed to be mediated by antioxidant property, impending neuroinflammation, alteration of monoaminergic responses, and preventing BDNF depletion. Abbreviations used: HEZA: Hydroethanolic extract of Zanthoxylum alatum seeds; LPS: Lipopolysaccharide; OFT: Open field test; FST: Forced swim test; TST: Tail suspension test; SPT: Sucrose preference test; LPO: Lipid peroxidation; NO: Nitric oxide; GSH: Glutathione; SOD: Superoxide dismutase; CAT: Catalase; GPx: Glutathione peroxidase; HPLC: High-performance liquid chromatography; NFκB: Nuclear factor-κB; Nrf2: Nuclear factor (erythroid-derived 2)-like 2; RT-PCR: Reverse transcription-polymerase chain reaction; BDNF: Brain-derived neurotrophic factor; TrkB: Tropomyosin receptor kinase B; 5-HT: 5-hydroxytryptamine; NE: Norepinephrine; DA: Dopamine; PCA: Perchloric acid; LC-ESI-MS/MS: Liquid chromatography–electrospray ionization–tandem mass spectrometry; ZA: Zanthoxylum alatum.