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.

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.

Implications of dealing with airborne substances and reactive oxygen species: what mammalian lungs, animals, and plants have to say?

A gas-exchange structure interacts with the environment and is constantly challenged by contaminants that may elicit defense responses, thus compromising its primary function. It is also exposed to high concentrations of O(2) that can generate reactive oxygen species (ROS). Revisiting the lung of mammals, an integrative picture emerges, indicating that this bronchi-alveolar structure deals with inflammation in a special way, which minimizes compromising the gas-exchange role. Depending on the challenge, pro-inflammatory or antiinflammatory responses are elicited by conserved molecules, such as surfactant proteins A and D. An even broader picture points to the participation of airway sensors, responsive to inflammatory mediators, in a loop linking the immunological and nervous systems and expanding the role played by respiratory organs in functions other than gas-exchange. A byproduct of exposure to high concentration of O(2) is the formation of superoxide ( ), hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(•)), and other ROS, which are known to be toxic to different types of cells, including the lung epithelium. A balance between antioxidants and oxidants exists; in pulmonary epithelial cells high intracellular and extracellular levels of antioxidants are found. Antioxidant adaptations related to plant and animal life-styles involve a broad range of overlapping strategies based on well-conserved molecules. Glutathione (GSH) is an abundant and ubiquitous thiol-tripeptide antioxidant, also present in lungs, whose role in providing information on the intracellular redox state of animals and plants is well established. In these organisms, GSH influences gene expression associated with stress, maximizing defense responses. Several enzymatic antioxidants, such as glutathione peroxidase (GPx), glutathione reductase, glutathione S-transferase, and glucose 6-phosphate dehydrogenase participate in the redox system; in animals that are stress-tolerant GPx is a key element against oxidative assaults. Most importantly, alternative roles of ROS as signaling molecules have been found in all plants and animals. For example, alveolar macrophages produce that act as second messengers, in addition to having a bactericidal role. The nonradical ROS H(2)O(2) signals inflammation in mammalian lungs, apoptosis in different animal tissues, and is also involved in stomatal closure, root development, gene expression, and defense responses of plants. Antioxidant adaptations in some water-breathing animals involve the excretion of H(2)O(2) by diffusion through gas-exchange structures. The fine balance among a multitude of factors and cells makes the difference between damage and protection in animals and plants. Knowledge about the mechanisms and consequences of these molecular interactions is now starting to be integrated.