Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.

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Environmental challenges are part of daily life for any individual. In fact, stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Using a broad definition of pathology, we here review the “neuropathology of stress” and focus on structural consequences of stress exposure for different regions of the rodent, primate and human brain. We discuss cytoarchitectural, neuropathological and structural plasticity measures as well as more recent neuroimaging techniques that allow direct monitoring of the spatiotemporal effects of stress and the role of different CNS structures in the regulation of the hypothalamic–pituitary–adrenal axis in human brain. We focus on the hypothalamus, hippocampus, amygdala, nucleus accumbens, prefrontal and orbitofrontal cortex, key brain regions that not only modulate emotions and cognition but also the response to stress itself, and discuss disorders like depression, post-traumatic stress disorder, Cushing syndrome and dementia.

Exposure to stress during the sensitive period of early-life increases the risk to develop cognitive impairments and psychopathology later in life. In addition, early-life stress (ES) exposure, next to genetic causes, has been proposed to modulate the development and progression of Alzheimer's disease (AD), however evidence for this hypothesis is currently lacking. We here tested whether ES modulates progression of AD-related neuropathology and assessed the possible contribution of neuroinflammatory factors in this. We subjected wild-type (WT) and transgenic APP/PS1 mice, as a model for amyloid neuropathology, to chronic ES from postnatal day (P)2 to P9. We next studied how ES exposure affected; 1) amyloid β (Aβ) pathology at an early (4month old) and at a more advanced pathological (10month old) stage, 2) neuroinflammatory mediators immediately after ES exposure as well as in adult WT mice, and 3) the neuroinflammatory response in relation to Aβ neuropathology. ES exposure resulted in a reduction of cell-associated amyloid in 4month old APP/PS1 mice, but in an exacerbation of Aβ plaque load at 10months of age, demonstrating that ES affects Aβ load in the hippocampus in an age-dependent manner. Interestingly, ES modulated various neuroinflammatory mediators in the hippocampus of WT mice as well as in response to Aβ neuropathology. In WT mice, immediately following ES exposure (P9), Iba1-immunopositive microglia exhibited reduced complexity and hippocampal interleukin (IL)-1β expression was increased. In contrast, microglial Iba1 and CD68 were increased and hippocampal IL-6 expression was decreased at 4months, while these changes resolved by 10months of age. Finally, Aβ neuropathology triggered a neuroinflammatory response in APP/PS1 mice that was altered after ES exposure. APP/PS1 mice exhibited increased CD68 expression at 4months, which was further enhanced by ES, whereas the microglial response to Aβ neuropathology, as measured by Iba1 and CD11b, was less prominent after ES at 10months of age. Finally, the hippocampus appears to be more vulnerable for these ES-induced effects, since ES did not affect Aβ neuropathology and neuroinflammation in the entorhinal cortex of adult ES exposed mice. Overall, our results demonstrate that ES exposure has both immediate and lasting effects on the neuroinflammatory response. In the context of AD, such alterations in neuroinflammation might contribute to aggravated neuropathology in ES exposed mice, hence altering disease progression. This indicates that, at least in a genetic context, ES could aggravate AD pathology.

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