Phytochemicals encouraging neurotrophic pathways: brain-derived neurotrophic factors as molecular targets in depression

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 9. doi: 10.1007/s00210-025-04298-2. Online ahead of print.

ABSTRACT

A complex neuropsychiatric disorder, major depressive disorder (MDD), is linked to dysregulation of neurotrophic factors, neurotransmitter imbalances, and structural changes in the brain. A lack of brain-derived neurotrophic factor (BDNF) has been linked to the pathophysiology of depression. BDNF is critical for neuroplasticity, neuronal viability, and synaptic efficacy. The neurotrophic hypothesis of depression proposes that treatment strategies targeting the BDNF signaling pathway may be promising therapeutic strategies. While traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to modulate the expression of BDNF, their use is limited in effectiveness, and a delayed onset of action occurs in many patients. Recent studies have focused on the possibility of the use of phytochemicals as antidepressant agents to target the BDNF pathway. Phytochemicals such as curcumin, resveratrol, quercetin, EGCG, hesperidin, and baicalin have demonstrated neuroprotective and antidepressant-like properties by modulating several key signaling pathways, including the PI3K/Akt/mTOR, MAPK/ERK, and NF-κB/CREB pathways. These compounds increase BDNF expression, promote synaptic plasticity, and mitigate neuroinflammation, contributing to improved mood and cognitive function. Although phytochemicals show considerable preclinical and clinical activity, their clinical usage is limited and characterized by several problems, such as poor bioavailability, poor blood‒brain barrier permeability, and variability in therapeutic response. Several formulation strategies, such as structural modifications and nanoencapsulation, are being explored to improve their pharmacokinetic profiles. These results also highlight the need for larger clinical trials, combination therapies with pharmaceuticals, and mechanistic studies that may clarify the role of phytochemicals in establishing these products as effective and well-tolerated treatments for depression. This narrative review addresses the gap in understanding how plant-derived bioactive compounds can modulate neurotrophic pathways in depression and explores emerging strategies for translating these findings into therapies.

PMID:40490523 | DOI:10.1007/s00210-025-04298-2