Antioxidant Activity of Fluoxetine and Vortioxetine in a Non-Transgenic Animal Model of Alzheimer’s Disease

Abstract

Depression is a risk factor for the development of Alzheimer’s disease (AD). A neurobiological and clinical continuum exists between AD and depression, with neuroinflammation and oxidative stress being involved in both diseases. Second-generation antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are currently investigated as neuroprotective drugs in AD. By employing a non-transgenic AD model, obtained by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ) oligomers in 2-month-old C57BL/6 mice, we recently demonstrated that the SSRI fluoxetine (FLX) and the multimodal antidepressant vortioxetine (VTX) reversed the depressive-like phenotype and memory deficits induced by Aβ oligomers rescuing the levels of transforming growth factor-β1 (TGF-β1). Aim of our study was to test FLX and VTX for their ability to prevent oxidative stress in the hippocampus of Aβ-injected mice, a brain area strongly affected in both depression and AD. The long-term intraperitoneal (i.p.) administration of FLX (10 mg/kg) or VTX (5 and 10 mg/kg) for 24 days, starting 7 days before Aβ injection, was able to prevent the over-expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (Nox2) induced by Aβ oligomers. Antidepressant pre-treatment was also able to rescue the mRNA expression of glutathione peroxidase 1 (Gpx1) antioxidant enzyme. FLX and VTX also prevented Aβ-induced neurodegeneration in mixed neuronal cultures treated with Aβ oligomers. Our data represent the first evidence that the long-term treatment with the antidepressants FLX or VTX can prevent the oxidative stress phenomena related to the cognitive deficits and depressive-like phenotype observed in a non-transgenic animal model of AD.

RETRACTED: Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment

“…It has also been demonstrated that wounded tissues are characterized by elevated oxidative stress, presenting high levels of MDA paralleled by decreased levels of antioxidants [56,59,60]. Second-generation antidepressants, such as FLX, are also known to exert an antioxidant activity both in vitro and in vivo [22,61]. Based on the evidence described above, we investigated the tissue levels of MDA, GSH, SOD, and GPx in diabetic rats subjected to our different experimental conditions.…”

“…Hence, serotonin, or selective serotonin reuptake inhibitors (SSRIs), have been examined to promote wound healing in experimental models [20]. Fluoxetine (FLX), the first antidepressant developed in the class of the SSRIs, represents one of the main first-line medications used for major depression, and is also known to reduce inflammation [21] and oxidative stress [22]. FLX, administered intraperitoneally, has also been shown to be able to enhance the wound healing process in chronically stressed Wistar rats [23].…”

Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study

“…Numerous preclinical and clinical studies have further suggested that the consumption of dietary antioxidants such as ascorbic acid, tocopherol, beta-carotene, polyphenols, isoflavonoids, and omega-3 polyunsaturated fatty acids significantly improves depressive symptoms in patients [ 58 , 59 , 60 , 61 ]. Indeed, conventional antidepressant medications including doxepin, fluoxetine, and vortioxetine endowed with oxidative and nitrosative scavenging activities have a protective effect [ 62 ].…”

Unveiling the Hidden Therapeutic Potential of Carnosine, a Molecule with a Multimodal Mechanism of Action: A Position Paper

“…There is continually increasing evidence that inflammation [ 45 , 46 , 47 ], oxidative stress [ 48 , 49 , 50 ], and aberrant aggregation and accumulation of proteins [ 51 , 52 ] significantly contribute to numerous systemic and neurodegenerative disorders such as diabetes mellitus type 2 (T2DM) [ 53 , 54 ], PD [ 55 , 56 ], and AD [ 57 , 58 , 59 ]. In this context, the well-known and frequently cited anti-oxidant, anti-inflammatory, and anti-aggregant activities of carnosine, which underline its multimodal mechanism of action, have been considered.…”