Exploring the Therapeutic Potential of Phytochemicals in Modulating Synaptic Plasticity and Neuroinflammation in Depression

Depression is a debilitating psychiatric disorder characterized by symptoms such as anhedonia (loss of pleasure), anxiety, persistent sadness, and suicidal ideation. In the past few years, the prevalence rate of depression has been continuously rising, representing a significant public health concern. This growing burden is largely attributed to the failure of current pharmacotherapies and the lack of novel and effective therapeutic targets. This review highlights two major neurobiological mechanisms central to the pathophysiology of depression: neuroinflammation and impaired synaptic plasticity. Particular emphasis is placed on the Sonic hedgehog (Shh) signaling pathway as a key regulator of synaptic plasticity, as well as the polarization dynamics of microglia and astrocytes, which are central mechanisms underlying neuroinflammation. Within this framework, we provide a narrative overview of recent preclinical studies that investigate the therapeutic potential of phytochemicals. The studies discussed were selected based on their relevance to the topic rather than a predefined systematic review protocol. These natural compounds have demonstrated the capacity to modulate neuroinflammation, enhance synaptic protein expression, promote neurogenesis, and improve neuronal connectivity. Several phytochemicals have demonstrated considerable potential as adjunctive and supplementary agents in managing symptoms of depression. Collectively, emerging findings suggest that phytochemicals represent a viable approach for developing next-generation antidepressant strategies that target both inflammatory and synaptic dysfunction.