Neuroinflammation, Oxidative Stress, and the BDNF–TrkB–mTOR Axis in Depression

Abstract

Depression is a multidimensional mental disorder that extends beyond changes in mood and adversely affects cognitive functioning, social adjustment, quality of life, and physical health. Although its biological basis was long interpreted primarily through the monoamine hypothesis, current evidence indicates that depression is too complex to be explained by alterations in a single neurotransmitter system. In recent years, impaired neuronal plasticity, disruption of neurotrophic support mechanisms, neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial-cell responses have emerged as central processes in the pathophysiology of depression. In particular, the role of brain-derived neurotrophic factor (BDNF) in neuronal survival, synaptic plasticity, dendritic development, and hippocampal neurogenesis provides an important framework for understanding the cellular and molecular basis of the disorder. At the same time, microglial and astrocytic activation, increased production of pro-inflammatory cytokines, oxidative damage, and disturbances in mitochondrial energy metabolism may compromise neuronal network integrity and thereby contribute to both the onset and persistence of depression. This review provides an integrated account of the roles of BDNF and related neurotrophic factors, neuroinflammation, oxidative stress, mitochondrial dysfunction, experimental models of depression, and contemporary therapeutic approaches. It also discusses the value of histological, immunohistochemical, molecular, and biomarker-based strategies for identifying biological subtypes of depression and developing more targeted treatments.