Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BEC), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, is itself regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BEC, protect the integrity of the BBB and its ability to transport insulin. Most of insulin’s known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer’s disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain.

Glutathione (GSH) is the most abundant antioxidant in aerobic cells, present in micromolar (microM)-concentrations in bodily fluids and in millimolar (mM) concentrations in tissue. GSH is critical for protecting the brain from oxidative stress, acting as a free radical scavenger and inhibitor of lipid peroxidation. GSH also participates in the detoxification of hydrogen peroxide by various glutathione peroxidases. The ratio of reduced GSH to oxidized GSH (GSSG) is an indicator of cellular health, with reduced GSH constituting up to 98% of cellular GSH under normal conditions. However, the GSH/GSSG ratio is reduced in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). Measuring the GSH/GSSG ratio in pathological tissues and experimental models thereof in comparison to the results in controls is an excellent way to assess potential therapeutics efficacy in maintaining cellular redox potential. The availability of UV/Visible instruments equipped with 96-well plate readers as common laboratory equipment has made measuring the GSH/GSSG ratio on multiple samples a manageable procedure.

Nitric oxide (NO), plays multiple roles in the nervous system. In addition to regulating proliferation, survival and differentiation of neurons, NO is involved in synaptic activity, neural plasticity, and memory function. Nitric oxide promotes survival and differentiation of neural cells and exerts long-lasting effects through regulation of transcription factors and modulation of gene expression. Signaling by reactive nitrogen species is carried out mainly by targeted modifications of critical cysteine residues in proteins, including S-nitrosylation and S-oxidation, as well as by lipid nitration. NO and other reactive nitrogen species are also involved in neuroinflammation and neurodegeneration, such as in Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, Friedreich ataxia, and Huntington disease. Susceptibility to NO and peroxynitrite exposure may depend on factors such as the intracellular reduced glutathione and cellular stress resistance signaling pathways. Thus, neurons, in contrast to astrocytes, appear particularly vulnerable to the effects of nitrosative stress. This article reviews the current understanding of the cytotoxic versus cytoprotective effects of NO in the central nervous system, highlighting the Janus-faced properties of this small molecule. The significance of NO in redox signaling and modulation of the adaptive cellular stress responses and its exciting future perspectives also are discussed.

Alzheimer's disease (AD) brains are characterized by accumulation of amyloid-ß protein (Aβ) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Aß accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Aß. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Aβ, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Aß, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Aß influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brainto-blood transporter of Aß, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Aß. Thus, inflammation potentially increases brain levels of Aß by three mechanisms: increased influx, decreased efflux, and increased neuronal production.