DOI: 10.62425/jlasp.1930657 ISSN: 2791-8645

Impact of Levetiracetam on Hypothalamic-Pituitary-Adrenal Axis Dysregulation, Anxiety-, and Depressive-Like Behaviors in Doxorubicin-Treated Mice

Mehmet Öz, Fatma Nur Bilgiç
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Doxorubicin (DOX) is a highly effective chemotherapeutic agent, yet its clinical utility is frequently compromised by severe neurotoxicity, manifesting as anxiety and depressive-like behaviors. This study investigated the neuroprotective efficacy of the antiepileptic drug levetiracetam (LEV) against DOX-induced affective disorders and explored the underlying neuroinflammatory, oxidative, and neuroendocrine mechanisms. Male BALB/c mice were randomly assigned to Control, DOX, DOX+LEV, and LEV groups. A single intraperitoneal injection of DOX (25 mg/kg) was utilized to induce neurotoxicity, while LEV (100 mg/kg/day) was administered over five consecutive days. Affective behaviors were evaluated using the open field (OF) and forced swim tests (FST). Hippocampal tumor necrosis factor-alpha (TNF-α) and glutathione (GSH) concentrations, alongside serum adrenocorticotropic hormone (ACTH) and cortisol levels, were quantified biochemically. DOX exposure precipitated severe anxiogenic and depressive-like phenotypes, evidenced by significantly reduced center exploration in the OF and increased immobility in the FST, independent of locomotor impairment. These behavioral deficits were mechanically coupled with marked hippocampal GSH depletion, elevated central TNF-α, and systemic hypothalamic-pituitary-adrenal (HPA) axis hyperactivation. Crucially, LEV co-administration completely abrogated the DOX-induced behavioral dysfunctions. This psychotropic efficacy was directly mirrored by the restoration of hippocampal oxidative-inflammatory homeostasis and the strict normalization of systemic ACTH and cortisol levels. DOX triggers affective disturbances driven by a pathological triad of neuroinflammation, oxidative stress, and neuroendocrine dysregulation. LEV effectively counteracts these cascades, highlighting its strong translational potential as an adjunctive therapy to mitigate chemotherapy-induced neuropsychiatric complications.

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