Paeoniflorin and depression: a comprehensive review of underlying molecular mechanisms.

Depression is one of the common mental disorders that often leads to persistent low mood, feelings of sadness or a sense of hopelessness, disinterest, or lack of pleasure in most day-to-day things. Depression is a leading cause of disability worldwide and a major contributor to the global burden of disease. Depression is a multifactorial disorder involving several interlinked pathways. A decrease in BDNF impairs neuroplasticity and synaptic function. Overactivation of the HPA axis elevates cortisol and disrupts mood regulation. Whereas/TLR-4/NF-κB activation triggers neuroinflammation, while NLRP3 inflammasome activation induces pyroptosis, promoting neuronal damage. Besides this, oxidative stress from ROS/antioxidant imbalance leads to neuronal damage and exacerbates neuroinflammatory responses. Moreover, reduced biogenic amines (like serotonin and dopamine) weaken mood regulation, and increased glutamatergic transmission leads to excitotoxicity. Together, these alterations contribute to the onset and progression of depression, necessitating a multifaceted approach. Paeoniflorin is a monoterpene glycoside isolated from the aqueous extract of the dry root of Paeonia species such as Paeonia lactiflora, Paeonia suffruticosa, and Paeonia veitchii. It exhibits a wide range of pharmacological activities, including antidepressant. anti-inflammatory, antioxidant, anticonvulsive, analgesic and hepatoprotective activities. Various reports have delineated that paeoniflorin exerts antidepressant effects by modulating the crucial mediators implicated in the pathophysiology of depression, including BDNF, CREB, NF-κB, TLR-4, NLRP3, HPA axis, ROS, serotonin, glutamate, mTOR, HMGB1, caspases, and SNARE proteins, among others, thereby providing a multitargeted defense against depression. Considering the potential of paeoniflorin in modulating these mediators, the current review is structured to explore the mechanistic interplay among these pathways in mediating its antidepressant effects.