Depression is a serious mental health disorder that can deeply affect a person’s quality of life, and the importance of treatment for depression cannot be overstated. The aim of this study is to compare ultrasonication procedure as green method and thin film hydration technique as conventional way for preparation of niosome to increase venlafaxine HCl brain delivery and investigate BDNF (Brain-derived neurotrophic factor) gene expression. Both approaches provided well-defined sphere particles; however, the green method (ultrasonication) manufactured smaller particle size (96.93 ± 3.82 nm), narrower size distribution (0.206 ± 0.006) niosomes with a higher entrapment efficiency (58.06 ± 1.45%) than the conventional method (p < 0.05). Moreover, the cytotoxicity examination revealed that the ultrasonication method prepared safe formulation and exhibited greater cellular safety than pure venlafaxine significantly (p < 0.05). The quantity of venlafaxine acquired by the brain following oral administration from green niosome made via ultrasonication (1222.077 ± 109.692 ng/mL) was substantially more than that of the venlafaxine solution and conventional niosome (p < 0.05). Green niosome substantially decreased the immobility period in the force swim test (61.666 ± 5.085 sec) and tail suspension test (62.500 ± 5.319 sec) in comparison with conventional niosome and venlafaxine in animal model of depression (p < 0.05). Green niosomes enhance venlafaxine’s antidepressant effect over conventional methods. Accordingly, green and conventional venlafaxine-niosome as well as its simple solution reversed the decreased BDNF gene expression in maternally separated mice, albeit there was no difference between different formulations (p > 0.05). Consequently, it was discovered that oral green venlafaxine niosome was a viable preparation for the management of depression, given its pharmacokinetic profile and therapeutic effects in animals.
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