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

Abstract

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.

Keywords

• Affective disorders
• Hippocampus
• Hypothalamic-pituitary-adrenal axis
• Neuroinflammation
• Oxidative stress

Doksorubisin Uygulanan Farelerde Levetirasetamın HPA Ekseni Disregülasyonu, Anksiyete ve Depresyon Benzeri Davranışlar Üzerindeki Etkisi

Abstract

Doksorubisin (DOX) oldukça etkili bir kemoterapötik ajandır; ancak klinik faydası, anksiyete ve depresyon benzeri davranışlar şeklinde tezahür eden şiddetli nörotoksisite nedeniyle sıklıkla kısıtlanmaktadır. Bu çalışma, antiepileptik bir ilaç olan levetirasetamın (LEV) DOX'un indüklediği afektif bozukluklara karşı nöroprotektif etkinliğini araştırmış ve altta yatan nöroenflamatuvar, oksidatif ve nöroendokrin mekanizmaları incelemiştir. Erkek BALB/c fareleri rastgele Kontrol, DOX, DOX+LEV ve LEV gruplarına ayrılmıştır. Nörotoksisiteyi indüklemek amacıyla tek doz intraperitoneal DOX (25 mg/kg) enjeksiyonu kullanılmış olup, LEV (100 mg/kg/gün) ardışık beş gün boyunca uygulanmıştır. Afektif davranışlar, açık alan (OF) ve zorlu yüzme (FST) testleri kullanılarak değerlendirilmiştir. Hipokampal tümör nekrozis faktör-alfa (TNF-α) ve glutatyon (GSH) konsantrasyonlarının yanı sıra serum adrenokortikotropik hormon (ACTH) ve kortizol seviyeleri biyokimyasal olarak ölçülmüştür. DOX maruziyeti; lokomotor bozukluktan bağımsız olarak, OF'de merkez keşfinde anlamlı bir azalma ve FST'de hareketsizlik süresinde artış ile kanıtlandığı üzere, şiddetli anksiyojenik ve depresyon benzeri fenotipleri tetiklemiştir. Söz konusu davranışsal defisitler; belirgin hipokampal GSH tükenmesi, artmış santral TNF-α seviyeleri ve sistemik hipotalamus-hipofiz-adrenal (HPA) ekseni hiperaktivasyonu ile mekanistik olarak bağlantılı bulunmuştur. Kritik bir bulgu olarak, eş zamanlı LEV uygulaması DOX'un indüklediği davranışsal disfonksiyonları tamamen ortadan kaldırmıştır. Bu psikotropik etkinlik; hipokampal oksidatif-enflamatuvar homeostazın yeniden sağlanması ve sistemik ACTH ile kortizol düzeylerinin kesin bir şekilde normalleşmesiyle doğrudan paralellik göstermiştir. Sonuç olarak DOX; nöroenflamasyon, oksidatif stres ve nöroendokrin disregülasyondan oluşan patolojik bir triad tarafından yönlendirilen afektif bozuklukları tetiklemektedir. LEV, bu kaskadları etkili bir şekilde baskılayarak, kemoterapinin indüklediği nöropsikiyatrik komplikasyonları hafifletmeye yönelik adjuvan bir tedavi olarak taşıdığı güçlü translasyonel potansiyeli vurgulamaktadır.

Keywords

• Afektif bozukluklar
• Hipotalamus-hipofiz-adrenal ekseni
• Doksorubisin
• Levetirasetam
• Nöroenflamasyon

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