Peganum harmala L. seed extract attenuates anxiety and depression in rats by reducing neuroinflammation and restoring the BDNF/TrkB signaling pathway and monoamines after exposure to chronic unpredictable mild stress

Depression is a mental disorder characterised by persistent low mood, anhedonia and cognitive impairment that affects an estimated 3.8% of the world's population, including 5% of adults. Peganum harmala L. (P. harmala) is a medicinal plant and has been reported to be effective against Alzheimer's disease, Parkinson's disease and depression. The present study was aimed to evaluate the behavioral and pharmacological effects of P. harmala seed extract in rats exposed to chronic unpredictable mild stress (CUMS) in vivo and to investigate the mechanism of action. CUMS-exposed rats were treated with P. harmala extract (75 and 150 mg/kg, i.p.) for 2 weeks. HPLC analysis was used to determine the concentration of harmaline and harmine alkaloids in the extract. Heavy metal analysis in seeds was performed by ICP-MS. Our results showed that P. harmala at the dose of 150 mg/kg significantly reduced the depressive-like behaviors in CUMS-exposed rats, as evidenced by increased sucrose consumption in the sucrose preference test (SPT), decreased immobility time in the forced swim test (FST) and plasma corticosterone levels, increased the time spent in open arms in the elevated plus maze (EPM), and improved memory and learning in the passive avoidance test (PAT). In addition, P. harmala decreased monoamine oxidase-A (MAO-A) levels, and increased serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels in the brains of rats exposed to CUMS. P. harmala decreased the expression of the pro-inflammatory transcription factor nuclear factor-kappa B (NF-kappa B), and increased the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) in rat brain. Furthermore, P. harmala improved brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression in rat brain. In conclusion, P. harmala at a dose of 150 mg/kg is more effective in preventing depressive-like behavior in CUMS-exposed rats by improving neurotransmitter levels, reducing oxidative stress, suppressing neuroinflammation and activating the BDNF/TrkB pathway, all of which are important in the pathogenesis of depression.