Single subanesthetic dose of ketamine exerts antioxidant and antidepressive-like effect in ACTH-induced preclinical model of depression

Abstract

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-d-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O₂^·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O₂^.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.