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Axonal loss and neuro-inflammation are two early hallmarks of multiple sclerosis (MS), which is a chronic neurodegenerative disease of the central nervous system (CNS). Removing myelin and neuronal debris is a general role for microglia to maintain CNS homeostasis and to promote remyelination. However, during neuro-inflammation in MS two phenotypes of activated macrophages (M1 and M2) are present in active and chronic active MS lesions. They originate from bone marrow or the yolk sac and are named bone marrow-derived macrophages or resident microglia respectively. Several studies suggest a dual role for macrophages in MS, when they are activated they might play a neurotoxic or a neuroprotective role. A phenotypic switch of macrophages induces M1 macrophages in active MS lesions, which leads to an enhanced level of pro-inflammatory cytokines. Macrophages produce neurotrophic factors to communicate with neurons, which is essential to promote neuronal survival. Some of the current therapies for MS are based upon regulation of M1 and M2 macrophages, to reduce neuronal loss. We propose that macrophages play both a harmful and beneficial role in neuroregeneration in which clearance of debris and secretion of macrophage-derived cytokines results in neuronal protection. Conversely, ROS, NO and pro-inflammatory cytokines secreted by M1 macrophages promote neuronal damage. During MS the clearance of debris and the production of cytokines that promote neuronal survival might be inhibited.

1 april 2010, Item does not contain fulltext, A reduced sensitivity to glucocorticoids can affect the clinical effect of treatment with high-dose intravenous methylprednisolone in multiple sclerosis. We prospectively studied 27 multiple sclerosis patients who were treated with intravenous methylprednisolone. Before and after treatment in vitro stimulated TNF-alpha production in blood cells and the effect of in vitro administered glucocorticoids were determined as a measure of glucocorticoid sensitivity. The suppression of TNF-alpha production after intravenous methylprednisolone, and the in vitro suppressive effect of glucocorticoids prior to treatment was related to subsequent clinical improvement after intravenous methylprednisolone. The results suggest the existence of a partial glucocorticoid resistance, in a subgroup of multiple sclerosis patients, which may have implications for treatment efficacy.

Contains fulltext : 71055.pdf (publisher's version ) (Closed access), Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood-brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.

Contains fulltext : 71338.pdf (publisher's version ) (Closed access), Reactive oxygen species (ROS) play a pivotal role in the development of neuroinflammatory disorders, such as multiple sclerosis (MS). Here, we studied the effect of ROS on protein expression in brain endothelial cells (BECs) using proteomic techniques and show that long-term exposure to ROS induces adaptive responses in BECs to counteract an oxidative attack. ROS induce differential protein expression in BECs, among which is peroxiredoxin-1 (Prx1). To further study the role of Prx1 we established a BEC line overexpressing Prx1. Our data indicate that Prx-1 overexpression protects BECs from ROS-induced cell death, reduces adhesion and subsequent transendothelial migration of monocytes by decreasing intercellular adhesion molecule-1 expression, and enhances the integrity of the BEC layer. Interestingly, vascular Prx1 immunoreactivity was markedly upregulated in inflammatory lesions of experimental autoimmune encephalomyelitis (EAE) animals and active demyelinating MS lesions. These findings indicate that enhanced vascular Prx1 expression may reflect the occurrence of vascular oxidative stress in EAE and MS. On the other hand, it may function as an endogenous defense mechanism to inhibit leukocyte infiltration and counteract ROS-induced cellular injury.

Contains fulltext : 52765.pdf (publisher's version ) (Closed access), The blood-brain barrier (BBB) prevents the entrance of circulating molecules and immune cells into the central nervous system. The barrier is formed by specialized brain endothelial cells that are interconnected by tight junctions (TJ). A defective function of the BBB has been described for a variety of neuroinflammatory diseases, indicating that proper regulation is essential for maintaining brain homeostasis. Under pathological conditions, reactive oxygen species (ROS) significantly contribute to BBB dysfunction and inflammation in the brain by enhancing cellular migration. However, a detailed study about the molecular mechanism by which ROS alter BBB integrity has been lacking. Here we demonstrate that ROS alter BBB integrity, which is paralleled by cytoskeleton rearrangements and redistribution and disappearance of TJ proteins claudin-5 and occludin. Specific signaling pathways, including RhoA and PI3 kinase, mediated observed processes and specific inhibitors of these pathways prevented ROS-induced monocyte migration across an in vitro model of the BBB. Interestingly, these processes were also mediated by protein kinase B (PKB/Akt), a previously unknown player in cytoskeleton and TJ dynamics that acted downstream of RhoA and PI3 kinase. Our study reveals new insights into molecular mechanisms underlying BBB regulation and provides novel opportunities for the treatment of neuroinflammatory diseases.

Contains fulltext : 52796.pdf (publisher's version ) (Closed access), Reactive oxygen species contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. To counteract the detrimental effects of ROS the central nervous system is endowed with a protective mechanism consisting of enzymatic and non-enzymatic antioxidants. Expression of most antioxidant enzymes is regulated through the transcription factor nuclear factor-E2-related factor (Nrf2) and antioxidant response elements (ARE) in the genes encoding enzymatic antioxidants and is induced by oxidative stress. In brain tissue of MS patients, enhanced expression of Nrf2/ARE-regulated antioxidants is suggestive of the occurrence of oxidative stress in these lesions. Antioxidant therapy may therefore represent an attractive treatment of MS. Several studies have shown that antioxidant therapy is beneficial in vitro and in vivo in animal models for MS. However, the use of exogenous antioxidants for MS treatment has drawbacks, as large amounts of antioxidants are required to achieve functional antioxidant levels in the central nervous system. Therefore, the induction of endogenous antioxidant enzymes by activators of the Nrf2/ARE pathway may be an interesting approach to obtain sufficient levels of antioxidants to interfere with pathological processes underlying MS lesion formation. In this review we summarize and discuss the biological role, regulation and potential therapeutic effects of endogenous antioxidant enzymes in MS. We propose that antioxidants may inhibit the development and progression of MS lesions and may therefore represent an attractive therapeutic target for the treatment of MS and other oxidative stress-related neurological diseases.

Contains fulltext : 47726.pdf (publisher's version ) (Closed access), Elevated serum homocysteine has been associated with increased risk of Alzheimer's disease. Furthermore, elevated homocysteine levels are related to cognitive dysfunction in the elderly. The aim of the present study was to explore the disease specificity of the relation between serum total homocysteine levels and cognitive function. For this, we summarize data from several studies on homocysteine levels in both normal and pathological conditions performed in our laboratories and evaluate possible mechanisms of effects of elevated homocysteine levels in the central nervous system. Total homocysteine levels were measured in serum of: 1) healthy aging individuals; 2) patients with Alzheimer's and Parkinson's disease and patients with other cognitive disorders; and 3) patients with multiple sclerosis. Increased serum homocysteine concentration was related to worse cognitive performance over a 6-year period in the normal aging population (r=-0.36 to -0.14, p<0.01 for the Word learning tests; r=0.76, p<0.05 for the Stroop Colored Word test). Homocysteine was only increased in patients with Parkinson's disease on L-Dopa therapy (18.9 vs. 16.5 micromol/L in healthy controls), and not in dementia patients. Homocysteine was elevated in patients with progressive multiple sclerosis (15.0 micromol/L, n=39, compared to 12.0 micromol/L in 45 controls) and correlated to both cognitive and motor function (r=-0.33 and -0.33, p<0.05, respectively). The relationship between homocysteine and cognitive function in non-pathological and pathological situations indicates that changes in its levels may play a role in cognitive functioning in a broad spectrum of conditions.

Experimental allergic encephalomyelitis (EAE) serves as an animal model for certain neuroinflammatory diseases of the central nervous system, in particular multiple sclerosis (MS). EAE is accompanied by transient weakness or paralysis of hind limbs. We have investigated the effect of partial and transient conduction failure in the central nervous system on skeletal muscle function. At ∼2.5 days after development of maximal clinical signs, body and medial gastrocnemius muscle mass were lower (by ∼21 and 33%, respectively; P < 0.05) in EAE rats compared with controls. Fiber cross-sectional area was lower by 40-50% in all fiber types. Maximal force and power were substantially lower (by 58% and 73%) in EAE rats, as was the force normalized for muscle mass (35%). However, no such weakness was found when lower stimulation frequencies were used. Generation of similar submaximal forces was attributable to a slower relaxation in EAE muscles. This advantage for the EAE muscles was lost during repeated exercise. While fatigability was similar, the difference in relaxation rate between EAE and control disappeared in fatigue. Our data suggest that, as a result of central neuroinflammatory diseases, maximal performance of skeletal muscle is impaired but submaximal performance is relatively well maintained.