Pre- and post-natal melatonin administration partially regulates brain oxidative stress but does not improve cognitive or histological alterations in the Ts65Dn mouse model of Down syndrome

Abstract

Melatonin administered during adulthood induces beneficial effects on cognition and neuroprotection in the Ts65Dn (TS) mouse model of Down syndrome. Here, we investigated the effects of pre- and post-natal melatonin treatment on behavioral and cognitive abnormalities and on several neuromorphological alterations (hypocellularity, neurogenesis impairment and increased oxidative stress) that appear during the early developmental stages in TS mice. Pregnant TS females were orally treated with melatonin or vehicle from the time of conception until the weaning of the offspring, and the pups continued to receive the treatment from weaning until the age of 5 months. Melatonin administered during the pre- and post-natal periods did not improve the cognitive impairment of TS mice as measured by the Morris Water maze or fear conditioning tests. Histological alterations, such as decreased proliferation (Ki67+ cells) and hippocampal hypocellularity (DAPI+ cells), which are typical in TS mice, were not prevented by melatonin. However, melatonin partially regulated brain oxidative stress by modulating the activity of the primary antioxidant enzymes (superoxide dismutase in the cortex and catalase in the cortex and hippocampus) and slightly decreasing the levels of lipid peroxidation in the hippocampus of TS mice. These results show the inability of melatonin to prevent cognitive impairment in TS mice when it is administered at pre- and post-natal stages. Additionally, our findings suggest that to induce pro-cognitive effects in TS mice during the early stages of development, in addition to attenuating oxidative stress, therapies should aim to improve other altered processes, such as hippocampal neurogenesis and/or hypocellularity.

Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials

“…Similarly, despite melatonin-exerted neuroprotection and induced pro-cognitive effects observed when it was administered during adult stages to Ts65Dn mice, its administration during pre-and postnatal stages did not prevent or reduce the cognitive impairment of these animals. The differences found between the administration of this indoleamine to Ts65Dn mice during early and late stages were probably due to the different doses used in each case, or to the well-known differences in pharmacokinetics between infancy and adulthood [80].…”

“…The Ts65Dn mouse, the best characterized and the most commonly used model of DS, shows increased OS (lipid peroxidation and protein carbonylation) and mitochondrial dysfunction in the hippocampus and cortex [77][78][79][80][81][82][83], that affects brain structure and function [75]. Although, to the best of our knowledge, oxidative DNA damage has not been studied in the brain of this model, it has been demonstrated that other cell types such as satellite cells of skeletal myofibers and hematopoietic stem cells accumulate oxidative DNA damage and prematurely develop a senescent phenotype in the Ts65Dn mouse [84][85][86].…”

Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

“…It was reported that melatonin rescued the neurogenesis suppression in the Ts65Dn (TS) mice by increasing the density and activity of glutamatergic synapses [ 112 ]. Nevertheless, in another study, it was shown that melatonin had no effect on the improvement of neurogenesis and behavioral outcomes in TS mice, but only regulated the DS-induced oxidative stress [ 113 ] ( Table 12 ).…”

Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

“…Levels of oxidative stress, i.e., high ratio between SOD1 and GPx, correlated with cognitive phenotype [268]. However, a recent study showed that administration of melatonin at the pre-and post-natal stages partially alleviated oxidative stress but did not improve cognitive function in a mouse model [269]. The process of programmed cell death was found to coincide with increased levels of oxidative stress, compared to control cells.…”