Hesperidin Attenuates Chronic Stress-Induced Depression via 5-HT2A-Linked Modulation of Neurochemical, Oxidative, and Inflammatory Pathways: Experimental and In Silico Evidence.

Authors

Mimansa Kandhwal, Amarjot Kaur Grewal, Varinder Singh, Ojashvi Sharma, Heena Khan, Manjinder Singh, Amit Kumar, Thakur Gurjeet Singh, Tanveer Singh, Sheikh F Ahmad, Haneen A Al-Mazroua, Gamaleldin I Harisa

Published in

Neurochemical research. Volume 50. Issue 5. Pages 310. Sep 29, 2025. Epub Sep 29, 2025.

Abstract

Depression is associated with monoaminergic dysregulation, oxidative stress, and neuroinflammation, with the 5-hydroxytryptamine 2 A (5-HT2A) receptor playing a key role. The present study investigated the antidepressant-like potential of hesperidin (HSP), a citrus-derived flavonoid, administered chronically (100 or 200 mg/kg, orally once daily for 21 days) in mice exposed to chronic unpredictable mild stress (CUMS). These effects were further explored through 5-HT2A-associated neurochemical and molecular mechanisms, highlighting its role in stress-related neuroprotection. Exposure to CUMS produced depressive-like behavior, accompanied by increased corticosterone, oxidative stress, inflammation, and depletion of 5-HT and dopamine. Treatment with HSP effectively reversed these alterations by restoring sucrose preference, reducing immobility time in the forced swim test, and normalizing locomotor activity in the open field test. At the neurochemical level, HSP treatment reinstated 5-HT and dopamine levels, reduced corticosterone, and attenuated oxidative (MDA, GSH, SOD, catalase) and inflammatory (NF-κB, IL-1β, IL-6, TNF-α) markers. Moreover, HSP improved neuronal architecture, underscoring its neuroprotective potential. Co-administration of the 5-HT2A receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 5 mg/kg, subcutaneously, once daily during the 21-day protocol) abolished HSP's effects, implicating 5-HT2A antagonism in its mechanism. In silico studies confirmed strong and stable binding of HSP to 5-HT2A receptors (- 72.99 kcal/mol), with key interactions involving Trp151, Asp155, Ser159, and Phe340. Molecular dynamics simulations (100 ns) supported complex stability. These results suggest that HSP exerts antidepressant-like effects by modulating 5-HT2A receptors, restoring HPA axis balance, reducing oxidative stress and neuroinflammation, and normalizing monoaminergic function.

PMID:
41021139
Bibliographic data and abstract were imported from PubMed on 29 Sep 2025.

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