From Xenobiotic Exposure to Neuroinflammation: Mechanisms Linking Lipopolysaccharide Signaling to Depressive-like Behavior
Depression is increasingly recognized as a multifactorial disorder involving immune, metabolic, and neurobiological disturbances that extend beyond classical monoaminergic hypotheses. Among xenobiotic-based experimental approaches, lipopolysaccharide (LPS) has become a valuable tool for investigating how peripheral inflammatory stimuli are translated into central neurobiological dysfunction. This narrative review aimed to integrate current evidence regarding the mechanisms by which LPS-induced neuroimmune activation contributes to depression-related phenotypes and to discuss the translational relevance of these findings. Literature searches were performed in PubMed, ScienceDirect, and Google Scholar, focusing on studies addressing inflammatory signaling, oxidative imbalance, inflammasome activation, neurotransmitter dysfunction, and experimental modeling strategies. Current evidence suggests that LPS-induced neuroinflammation involves a dynamic interaction between peripheral immune signaling, mitochondrial dysfunction, redox imbalance, and glial activation, establishing self-amplifying mechanisms capable of sustaining chronic inflammatory states. Such alterations profoundly affect kynurenine metabolism, glutamatergic homeostasis, and reward-related neurotransmission, thereby contributing to synaptic dysfunction and behavioral impairment. Experimental findings obtained from animal, cellular, and computational platforms further support the emergence of integrated therapeutic strategies targeting multiple neuroimmune pathways. Collectively, these observations reinforce the concept that neuroinflammation represents a central biological interface linking xenobiotic exposure to depressive-like behavior.