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.
Highlights
Alzheimer’s disease (AD) represents a type of dementia affecting memory, global cognitive function, and behavior, severe enough to interfere with activities of daily living (Kumar et al, 2021)
We examined the effects of Aβ oligomers on the mRNAs levels of the pro-oxidant enzymes inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (Nox2) in the hippocampus (Figure 1), a brain area strongly affected in depression and AD (Villa et al, 2016; Setti et al, 2017)
Long-term i.p. treatment with FLX or VTX, administered at the same dose of 10 mg/kg, was able to abolish the over-expression of iNOS Aβinduced (p < 0.05 vs. Aβ oligomers), whereas the lower dose of VTX (5 mg/kg) did not reach a statistically significant difference, even though a trend in iNOS mRNA enzyme expression decrease was observed
Summary
Alzheimer’s disease (AD) represents a type of dementia affecting memory, global cognitive function, and behavior, severe enough to interfere with activities of daily living (Kumar et al, 2021) This disease presents neuropsychiatric symptoms, such as depression, along with neurodegeneration, neuroinflammation, and oxidative stress phenomena (Caruso et al, 2021). Depression represents a risk factor for AD development, while the occurrence of depressive symptoms significantly increases the conversion from mild cognitive impairment (MCI) into AD (Petersen et al, 2014) It is well-known that amyloid-β (Aβ), the peptide involved in the pathogenesis of AD, can undergo aggregation, starting with soluble monomers and forming species characterized by higher molecular weight such as oligomers, protofibrils, and mature fibrils (Brorsson et al, 2010). Markers of oxidative stress have been found in AD animal models before plaques deposition as well as in brain, plasma, and erythrocytes from MCI and AD patients (Glenner and Wong, 1984; Minati et al, 2009), suggesting that redox imbalance and oxidative damage play a key role in an early stage of AD pathophysiology, as well as in the disease progression (Cheignon et al, 2018)
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