Chamomile Modulates Glucose Metabolism and Neuro-inflammation to Alleviate Stress-Induced Depression in Mice

Depression, a common psychiatric condition, is frequently associated with chronic stress. This research investigates the therapeutic benefit of chamomile (Matricaria chamomilla) against restraint stress (RS)-induced behavioral and neurobiological alterations in male mice. Animals were categorized into control, RS, and RS + chamomile (Cm) groups. Behavioral evaluation (open field, rotarod, catalepsy, memory test), histopathology, integrity of the blood-brain barrier, and gene expression profiling were done. In silico ProTox analysis confirmed the non-toxicity of chamomile compounds, including chamazulene, which also complies with Lipinski's Rule of Five, indicating drug-like properties. Molecular docking identified robust interactions between chamazulene and prominent stress-related and other relevant targets like IFN-γ, IL-6, caspase-3, BDNF, and GLUT-1. RS exposure interfered with locomotor activity, evoked neuroinflammation, apoptosis, and compromised neuronal-glial function. Treatment with chamomile greatly enhanced locomotor function and posture, decreased catalepsy latency test, and normalized neuronal architecture. Immunofluorescence staining and transcriptional analysis indicated that chamomile suppressed pro-inflammatory cytokines (IFN-γ, IL-6), the apoptotic marker Caspase-3, and increased neurotrophic and neuronal markers (BDNF, NeuN, GFAP) and glycolytic enzymes (GLUT-1, HK-1, LDHA). These results indicate that chamomile has neuroprotective actions by regulating RS-induced inflammation, apoptosis, and metabolic dysfunction. Although no remarkable effects were seen on body or brain-to-body weight ratio, chamomile exhibited powerful behavioral and molecular effects. Overall, the results highlight chamomile, particularly its active constituent chamazulene, as a promising candidate for alleviating restraint stress. However, further clinical validation is required to establish its therapeutic potential in neuropsychiatric disorders.