Chlorogenic Acid Attenuates Schizophrenia-Like Behavioral Deficits and Neuroinflammation in a Ketamine-Induced Mouse Model
Abstract
<title>Abstract</title> <p> Schizophrenia (SCZ) is a chronic neuropsychiatric disorder driven by neuroinflammation, microglial overactivation, and pro-inflammatory cytokine dysregulation. Despite antipsychotics, negative and cognitive symptoms remain inadequately treated. This study investigated the therapeutic potential of Chlorogenic Acid (CGA) in a ketamine-induced mouse model of SCZ using integrated <italic>in silico</italic> and <italic>in vivo</italic> approaches. Mice received sub-chronic ketamine (30 mg/kg) for 14 consecutive days to establish a SCZ-like phenotype. CGA (10, 50, or 100 mg/kg) or haloperidol (1 mg/kg) was co-administered. Behavioral outcomes, Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β), and neuronal integrity were assessed. Network pharmacology and molecular docking elucidated mechanisms. CGA significantly reversed ketamine-induced hyperlocomotion, social withdrawal, spatial memory deficits, and depressive-like behavior ( <italic>p</italic> < 0.001), with 10 mg/kg exhibiting the greatest efficacy comparable to haloperidol. CGA significantly suppressed hippocampal TNF-α and IL-1β at 10 mg/kg ( <italic>p</italic> < 0.001). Histopathological analysis demonstrated dose-dependent neuronal preservation in PFC, hippocampus, and striatum. Network pharmacology identified 196 targets enriched in TNF and IL-17 pathways, with IL6, TNF, IL1B, NFKB1, AKT1, and CASP3 as core hubs. Docking confirmed favorable CGA binding (GlideScores: −4.387 to − 6.6 kcal/mol). CGA at 10 mg/kg exerts broad-spectrum antipsychotic-like and neuroprotective effects via neuroinflammatory modulation, supporting its potential as a multi-target therapeutic candidate for the management of SCZ. </p>
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