Acute Experimental Allergic Encephalomyelitis Research Articles

Erythrocyte Plasma Membrane Lipid Composition Mirrors That of Neurons and Glial Cells in Murine Experimental In Vitro and In Vivo Inflammation.

Lipid membrane turnover and myelin repair play a central role in diseases and lesions of the central nervous system (CNS). The aim of the present study was to analyze lipid composition changes due to inflammatory conditions. We measured the fatty acid (FA) composition in erythrocytes (RBCs) and spinal cord tissue (gas chromatography) derived from mice affected by experimental allergic encephalomyelitis (EAE) in acute and remission phases; cholesterol membrane content (Filipin) and GM1 membrane assembly (CT-B) in EAE mouse RBCs, and in cultured neurons, oligodendroglial cells and macrophages exposed to inflammatory challenges. During the EAE acute phase, the RBC membrane showed a reduction in polyunsaturated FAs (PUFAs) and an increase in saturated FAs (SFAs) and the omega-6/omega-3 ratios, followed by a restoration to control levels in the remission phase in parallel with an increase in monounsaturated fatty acid residues. A decrease in PUFAs was also shown in the spinal cord. CT-B staining decreased and Filipin staining increased in RBCs during acute EAE, as well as in cultured macrophages, neurons and oligodendrocyte precursor cells exposed to inflammatory challenges. This regulation in lipid content suggests an increased cell membrane rigidity during the inflammatory phase of EAE and supports the investigation of peripheral cell membrane lipids as possible biomarkers for CNS lipid membrane concentration and assembly.

Angiopoietin-1 and C16 Peptide Attenuate Vascular and Inflammatory Responses in Experimental Allergic Encephalomyelitis.

Breakdown of normal blood-brain barrier function and accompanying vascular leakage are fundamental stages in the onset of multiple sclerosis and its animal counterpart, experimental allergic encephalomyelitis. In the present study, angiopoietin-1, an endothelial growth factor well known for its role in establishing and maintaining vascular integrity, and C16, a peptide that competitively binds to integrin αvβ3 expressed on endothelial cells, were used to treat acute experimental allergic encephalomyelitis in Lewis rats. Angiopoietin-1 was more effective than C16 for reducing inflammation-induced vascular leakage. Moreover, treatment with a combination of angiopoietin-1 and C16 resulted in greater effects, not only in alleviating inflammation and reducing axonal loss/demyelination but also in down-regulating pro-inflammatory cytokine expression and improving electrophysiological dysfunction, than treatment with either angiopoietin-1 or C16 alone. Different protective effects were observed with angiopoietin-1 and C16 treatment suggesting that these proteins target specific receptors to act through different pathways. Furthermore, angiopoietin-1 and C16 may form the basis of a promising therapeutic strategy for experimental allergic encephalomyelitis and multiple sclerosis.

Dose-Dependent Anti-Inflammatory and Neuroprotective Effects of anανβ3 Integrin-Binding Peptide

Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an α ν β3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease.

Antineuroinflammatory and neurotrophic effects of CNTF and C16 peptide in an acute experimental autoimmune encephalomyelitis rat model

Experimentalallergic encephalomyelitis (EAE) is an animal model for inflammatory demyelinating autoimmune disease, i.e., multiple sclerosis (MS). In the present study, we investigated the antineuroinflammatory/neuroprotective effects of C16, an ανβ3 integrin-binding peptide, and recombinant rat ciliary neurotrophic factor (CNTF), a cytokine that was originally identified as a survival factor for neurons, in an acute rodent EAE model. In this model, C16 peptide was injected intravenously every day for 2 weeks, and CNTF was delivered into the cerebral ventricles with Alzet miniosmotic pumps. Disease severity was assessed weekly using a scale ranging from 0 to 5. Multiple histological and molecular biological assays were employed to assess inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and gliosis in the brain and spinal cord of different groups. Our results showed that the EAE induced rats revealed a significant increase in inflammatory cells infiltration, while C16 treatment could inhibit the infiltration of leukocytes and macrophages down to 2/3–1/3 of vehicle treated EAE control (P < 0.05). The delayed onset of disease, reduced clinical score (P < 0.01) in peak stage and more rapid recovery also were achieved in C16 treated group. Besides impairing inflammation, CNTF treatment also exerted direct neuroprotective effects, decreasing demyelination and axon loss score (P < 0.05 versus vehicle treated EAE control), and reducing the neuronal death from 40 to 50% to 10 to 20% (P < 0.05). Both treatments suppressed the expression of cytokine tumor necrosis factor-α and interferon-γ when compared with the vehicle control (P < 0.05). Combined treatment with C16 and CNTF produced more obvious functional recovery and neuroprotective effects than individually treatment (P < 0.05). These results suggested that combination treatment with C16 and CNTF, which target different neuroprotection pathways, may be an effective therapeutic alternative to traditional therapy.

Neural precursors exhibit distinctly different patterns of cell migration upon transplantation during either the acute or chronic phase of EAE: A serial MR imaging study

As the complex pathogenesis of multiple sclerosis contributes to spatiotemporal variations in the trophic micromilieu of the central nervous system, the optimal intervention period for cell-replacement therapy must be systematically defined. We applied serial, 3D high-resolution magnetic resonance imaging to transplanted neural precursor cells (NPCs) labeled with superparamagnetic iron oxide nanoparticles and 5-bromo-2-deoxyuridine, and compared the migration pattern of NPCs in acute inflamed (n = 10) versus chronic demyelinated (n = 9) brains of mice induced with experimental allergic encephalomyelitis (EAE). Serial in vivo and ex-vivo 3D magnetic resonance imaging revealed that NPCs migrated 2.5 ± 1.3 mm along the corpus callosum in acute EAE. In chronic EAE, cell migration was slightly reduced (2.3 ± 1.3 mm) and only occurred in the lateral side of transplantation. Surprisingly, in 6/10 acute EAE brains, NPCs were found to migrate in a radial pattern along RECA-1(+) cortical blood vessels, in a pattern hitherto only reported for migrating glioblastoma cells. This striking radial biodistribution pattern was not detected in either chronic EAE or disease-free control brains. In both acute and chronic EAE brain, Iba1(+) microglia/macrophage number was significantly higher in central nervous system regions containing migrating NPCs. The existence of differential NPC migration patterns is an important consideration for implementing future translational studies in multiple sclerosis patients with variable disease.

Monitoring of acute axonal injury in the swine spinal cord with EAE by diffusion tensor imaging

To evaluate the ability of diffusion tensor imaging (DTI) to detect and monitor acute axonal injury in swine spinal cord with acute experimental allergic encephalomyelitis (EAE). Magnetic resonance imaging of the cervical spinal cord was performed in vivo at different time points through the onset and progression of EAE using a 3 Tesla clinical scanner. The DTI parameters were calculated in four separate regions of interest at the C2/C3 level. The quantitative DTI-pathology and DTI-clinical correlations were verified. In the monophasic acute course of EAE onset and progression, axial diffusivity (AD) decrease correlates with acute axonal injury (r = -0.84; P < 0.001). By contrast, radial diffusivity does not change and no demyelination in histopathology was detected. Moreover, a clear correlation between clinical disease and axial diffusivity was found in two swine EAE models (r = -0.86; P < 0.001 and r = -0.92; P < 0.001). AD corresponds with axonal injury in the absence of demyelination and may be a useful noninvasive tool to investigate the underlying pathogenic processes of multiple sclerosis and to monitor the effects of experimental treatments for axonal injury.

MRI of acute experimental allergic encephalomyelitis: correlation with pathology

Objective To investigate the MR imaging findings of acute experimental allergic encephalomyelitis(EAE) in correlation with pathology. Methods An EAE model was induced by intradermal inoculation with guinea pig CNS homogenate in 6 female Lewis rats.Another 6 rats served as control.The clinical presentation and body weight of the animals were recorded daily. Routine MRI,Gd-enhanced MRI were performed when EAE animals showed the initial symptoms. Uhrasmall superparamagnetic iron oxide(USPIO) colloid solution was also administrated intravenously and MRI was performed again after 24 hours. The brain was removed instantly after the second MR imaging. The pathological exams including HE staining,myelin sheath staining and prussian staining were performed.The imaging findings were observed in correlation with pathological results. Results The EAE rats showed decrease of body weight on the 6th to 7th day after inoculation,and the clinical symptoms appeared on the 10th to 11th day after inoculation.Routine MRI did not show any definite abnormalities.The Gd-enhanced MRI found the diffuse thickening and enhancement of brain meninges.The USPIO-enhanced MRI showedareas of low signal intensity at white matter of medulla oblongata on T2WI,and high signal intensity was observed at the corresponding area on T1 WI. Gradient T2 * WI found more foci of low signal intensity in eerebellar white matter besides the lesions in the brain stem.The range of abnormal signal intensity was larger in animal with higher clinical scores than that with lower score.There were no abnormal findings in control animaL The pathological exam found perivascular cuff in the brain white matter in EAE animals,some accompanied with adjacent demyelinatian. The prussian staining found blue particles within the cytoplasm of the macrophages around the lesion,which corresponded to the area of low signal intensity on T2WI.Conclusion USPIO-enhanced MRI could reveal acute EAE lesions which were not capable of being shown on routine MRI and Gd-enhanced MRI.It can image the macrophages around the lesions in vivo.USPIO is important for future research and application in MS patients. Key words: Encephalomyelitis,autoimmuc,experimental; Magnetic resonance imaging; Pathology

The distribution of immunoglobulins and albumin in the central nervous system in acute experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) was induced in young male Lewis rats. Immunohistochemical visualisation of albumin and IgG in the nervous tissue was performed at intervals after induction. The results were correlated to the histological appearance of the tissue. Albumin appeared in the tissue about day 10, 1-2 days before IgG. Within one day both proteins spread from sharply defined perivascular subpial locations to diffuse distribution throughout the tissue. Cellular inflammation was not seen until 3-4 days after extravasation of proteins. The cells also spread from perivascular locations to a diffuse infiltration of the tissue.

Effect of K+ channel blockers on the clinical course and histological features of experimental allergic encephalomyelitis.

Beneficial clinical effects of 4-aminopyridine (4-AP) in multiple sclerosis (MS) have been reported. The use of 4-AP in MS is based upon its ability to facilitate conduction in axons blocked by demyelination. This improvement is due to blocking of potassium (K+) channels in these fibres. Because K+ channels also play an important role in immune mechanisms successful treatment with K+ channel blockers in neuroimmunological diseases may have several causes. Therefore it seems important to study effects of K+ channel blockers in animal models of autoimmune disease. We studied the effects of 4-AP and quinidine on actively induced acute experimental allergic encephalomyelitis (EAE) in Lewis rats. There was no effect on the incidence of the disease. The severity of the disease was also unchanged although the disease duration was slightly diminished in the treated groups. Immunohistological comparison between the animals of different groups showed no differences. We conclude that 4-AP and quinidine are not capable of significantly changing the clinical course of EAE.

Pathological findings in rats with experimental allergic encephalomyelitis

The aim of this study was to establish an animal model of experimental allergic encephalomyelitis (EAE) and examine the basic pathological changes, as well as expression and distribution of MMP-2 and MMP-9, in Wistar rats. Tissue sections were processed for HE staining, Weil myelin staining, and modified Bielschowsky staining. Expression and distribution of glial fibrillary acidic protein (GFAP), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were detected with immunohistochemistry. We divided the EAE into five types, depending on pathological characteristics and clinical manifestations: acute EAE, relapsing-remitting EAE, progressive EAE, benign EAE, and asymptomatic EAE. Rats with acute EAE suffered from quick, severe attacks with widespread inflammatory cells and axonal loss. No demyelination or astrocytic hyperplasia was found around the lesions. Rats with relapsing-remitting EAE broke down twice, with many perivascular cuffs and demyelinating plaques in lesions; hyperplastic and hypertrophic astrocytes characterized old lesions and axonal loss was evident. Rats suffering from progressive EAE exhibited continuous aggravation without improvement, accompanied by perivascular cuffs, demyelination, increased gliocytes and axonal damage. Rats with benign EAE recovered to a normal state with obviously decreased inflammatory cells and almost entirely unaffected myelin and axons. Rats with asymptomatic EAE also had various pathological changes that were not coincident with their clinical manifestations. Elevated expression of MMP-2 and MMP-9 was concordant in different types of EAE, but the extent differed in each type of EAE. MMP-2 and MMP-9 can be expressed in the form of vascular endothelial cells, meninges, or accumulated inflammatory cells. Multiple clinical courses of disease were demonstrated in Wistar rat EAE, with attributes similar to multiple sclerosis (MS) in clinical and pathological characteristics. Elevated expression of MMP-2 and MMP-9 may play a role in some aspects of pathological changes in EAE, for example, destroying the blood-brain barrier, degrading the myelin sheath, and damaging axons.

Effects of amphetamine and cocaine on the development of acute experimental allergic encephalomyelitis in Lewis rats

The present experiment deals with the effects of amphetamine and cocaine on the development and course of experimental allergic encephalomyelitis (EAE) induced in Lewis rats. Rats were immunized at the age of eight weeks with purified myelin basic protein isolated from guinea pig brain in complete Freund's adjuvant. Drug administration and recording of EAE clinical signs was performed daily since day 1 post-immunization (PI). On day 14 and 28 PI, six rats per group were bled and sacrificed. Spinal cord was examined histologically for EAE lesions. In vivo administration of 0.5 and 1 mg/Kg of amphetamine or cocaine resulted in a dose-related enhancement of neurological and histological signs of acute EAE in comparison with control rats. Both drugs caused a reduction of latent period together with a delayed regression of neurological signs along with an increase in inflammation in the central nervous system in comparison with placebo. Human & Experimental Toxicology (2007) 26, 637-643.

Comparative study of preventive and therapeutic effects of IEM-1966 and memantine in rats with experimental allergic encephalomyelitis

We compared preventive and therapeutic effects of memantine, a selective blocker of NMDA-receptors, and IEM-1966, a blocker of both NMDA- and GluR1 AMPA-receptors, on the model of acute experimental allergic encephalomyelitis. Memantine in high doses prevented the development of experimental allergic encephalomyelitis only in 10% rats, slightly (by 1.4-1.5 times) moderated the neurological disturbances, and shortened the duration of the disease. In far lower doses, IEM-1966 prevented the development of experimental allergic encephalomyelitis in 50% rats, while in the affected rats it decreased the severity of neurological disturbances and duration of the disease by 3-4 times. When applied during the clinical phase of the disease, IEM-1966 decreased the severity of neurological disturbances and duration of the disease by 2.0-2.5 times predominantly in rats with mild and moderate course of experimental allergic encephalomyelitis.

Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity

Reactive oxygen species (ROS) play an important role in various events underlying multiple sclerosis (MS) pathology. In the initial phase of lesion formation, ROS are known to mediate the transendothelial migration of monocytes and induce a dysfunction of the blood-brain barrier (BBB). In this study, we describe the beneficial effect of the antioxidant alpha-lipoic acid (LA) on these phenomena. In vivo, LA dose-dependently prevented the development of clinical signs in a rat model for MS, acute experimental allergic encephalomyelitis (EAE). Clinical improvement was coupled to a decrease in leukocyte infiltration into the CNS, in particular monocytes. Monocytes isolated from the circulation of LA-treated rats revealed a reduced migratory capacity to cross a monolayer of rat brain endothelial cells in vitro compared with monocytes isolated from untreated EAE controls. Using live cell imaging techniques, we visualized and quantitatively assessed that ROS are produced within minutes upon the interaction of monocytes with brain endothelium. Monocyte adhesion to an in vitro model of the BBB subsequently induced enhanced permeability, which could be inhibited by LA. Moreover, administration of exogenous ROS to brain endothelial cells induced cytoskeletal rearrangements, which was inhibited by LA. In conclusion, we show that LA has a protective effect on EAE development not only by affecting the migratory capacity of monocytes, but also by stabilization of the BBB, making LA an attractive therapeutic agent for the treatment of MS.

Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of α4 integrin

To determine the efficacy of a small molecule inhibitor of alpha4 integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE). EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization. Animals received either saline (n = 12), anti-alpha4 integrin antibody (AN100226m; n = 12) or CT301 (n = 12). T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for cerebral inflammation and gadolinium enhancement. T1-weighted images were further analyzed to quantify this enhancement as a measure of blood-brain barrier integrity. Dissected CNS was evaluated for inflammation and demyelination. CT301 successfully reversed two clinical indicators of disease over the course of the treatment period. These animals showed decreased T2-weighted abnormalities, as well as a reduction in gadolinium leakage on T1-weighted images. Meningeal and perivascular inflammation was decreased by anti-alpha4 integrin treatments. CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in multiple sclerosis (MS).

Treatment of Mice with the Suppressor of Cytokine Signaling-1 Mimetic Peptide, Tyrosine Kinase Inhibitor Peptide, Prevents Development of the Acute Form of Experimental Allergic Encephalomyelitis and Induces Stable Remission in the Chronic Relapsing/Remitting Form

We have previously characterized a novel tyrosine kinase inhibitor peptide (Tkip) that is a mimetic of suppressor of cytokine signaling 1 (SOCS-1) and inhibits JAK2 phosphorylation of the transcription factor STAT1alpha. We show in this study that Tkip protects mice against experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis. Mice are immunized with myelin basic protein (MBP) for induction of disease. Tkip (63 mug) administered every other day suppressed the development of acute EAE in 75% of New Zealand White (NZW) mice. Furthermore, Tkip completely protected SJL/J mice, which where induced to get the relapsing/remitting form of EAE, against relapses compared with control groups in which >70% of the mice relapsed after primary incidence of disease. Protection of mice by Tkip was similar to that seen with the type I IFN, IFN-tau. Protection of mice correlated with lower MBP Ab titers in Tkip-treated groups as well as suppression of MBP-induced proliferation of splenocytes taken from EAE-afflicted mice. Cessation of Tkip and IFN-tau administration resulted in SJL/J mice relapsing back into disease. Prolonged treatment of mice with Tkip produced no evidence of cellular toxicity or weight loss. Consistent with its JAK2 inhibitory function, Tkip also inhibited the activity of the inflammatory cytokine TNF-alpha, which uses the STAT1alpha transcription factor. The data presented in this study show that Tkip, like the type I IFN, IFN-tau, inhibits both the autoreactive cellular and humoral responses in EAE and ameliorates both the acute and chronic relapsing/remitting forms of EAE.

Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis

Pixantrone is an immunesuppressor similar to mitoxantrone but with lower cardiotoxicity. We evaluated the effect of pixantrone on B cells and lymphomononuclear cells in the course of acute EAE. Pixantrone reduced the number of B cells and suppressed myelin basic protein (MBP) specific IgG production. In vitro, pixantrone induced apoptosis of rat B lymphocytes in a way similar to mitoxantrone. In addition, pixantrone inhibited antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-γ production, during EAE. These findings suggest a similar mechanism of action for pixantrone and mitoxantrone on the effector function of lymphomonocyte B and T cells.

Pathology‐guided MR analysis of acute and chronic experimental allergic encephalomyelitis spinal cord lesions at 1.5T

To directly correlate spinal cord pathology of guinea pigs with experimental allergic encephalomyelitis (EAE) to the MRI data obtained at 1.5T. Spinal cords from EAE animals were imaged in vivo with the following MRI sequences: T2-FSE, PD-FSE, fluid-attenuated inversion recovery (FLAIR)-FSE, T2-CSE, T1-CSE, T1-CSE + gadolinium-DTPA (Gd-DTPA), PD-CSE, and short-tau inversion recovery (STIR)-FSE. The spinal cords were removed and the lesions with specific pathological compositions were identified by histological analysis. Regions of interest (ROIs) were drawn on the corresponding MR images, and signal-to-noise ratios (SNRs) were measured for each MR sequence and compared with controls. The receiver operating characteristic (ROC) analysis of STIR-FSE and PD-CSE was able to differentiate tissue that contained cellular infiltrates with a high degree of accuracy. The SNRs of T2-FSE, STIR-FSE, T2-CSE, PD-CSE, and T1-CSE + Gd-DTPA were elevated in lesions that contained cellular infiltrates alone, whereas the SNRs of PD-CSE and T1-CSE + Gd-DTPA were reduced in demyelinated lesions that also contained inflammation. The SNR difference between the two lesion groups suggests that the combination of STIR-FSE, PD-CSE, and T1-CSE + Gd-DTPA sequences may be useful for differentiating inflammatory lesions containing demyelination from lesions with inflammation alone.

960. Gene-Based Delivery of Interferon-beta Is Efficacious in a Murine Model of Acute Experimental Allergic Encephalomyelitis

Experimental Allergic Encephalomyelitis (EAE) is a model of central nervous system (CNS) inflammation that ensues following immunization with certain CNS antigens, for example brain derived proteolipid or myelin basic protein. The course and clinical manifestations of EAE are similar to multiple sclerosis (MS) in humans and it has become an accepted animal model to study MS. There have been several reports in which Interferon-beta (IFN-b) protein has been shown to be effective in murine and rat models of EAE. It has also been shown that local CNS delivery of a plasmid DNA encoding IFN-b decreased the severity of the disease. The purpose of this study was to demonstrate that systemic expression of murine IFN-b (mIFN-b) following gene-based delivery of plasmid DNA to hind limb skeletal muscle is effective in reducing the clinical manifestations of disease in a rodent EAE model.

Pathogenesis of some neurological immune ultrastructural and morphometrical observations on rat thymus

Numerous studies on neuro-immuno-modulation indicate that the thymus is involved in many neurological diseases, including experimental allergic encephalomyelitis (EAE). Twenty Lewis rats were induced for EAE. At X, XII, XX and XXX days post-inoculation the animals were killed, and the thymus was recovered and harvested. Specimens of thymus were submitted to morphological light microscopy analysis (1% toluidine blue) and ultra-structural analysis (transmission electron microscopy). Significant morphometric data were collected by examining the images quantitatively and by statistically analysing the values. Our results show that the microenvironment of the thymus is severally involved in acute EAE. Thymocytes and reticular epithelial cells show many changes which are closely related to the pathogenesis of EAE. In particular we observed: (1) inside the cell an increase in intra-cytoplasmic vacuoles, and changes in the thickness of the nuclear membrane, mitochondria, rough endoplasmic reticulum, cellular inter-digitations and cellular electron-density; (2) outside the cell an increase in pericellular translucent halo, intercellular spaces, intercellular contacts and apoptotic and necrotic figures. The evidence of a thymic role in MS may suggest the intriguing therapeutic concept of thymectomy in the management of this neurological disease.

Flavonoids Influence Monocytic GTPase Activity and Are Protective in Experimental Allergic Encephalitis

In the chronic disabling disease multiple sclerosis (MS), migration of monocytes across the blood-brain barrier is a crucial step in the formation of new lesions in the central nervous system (CNS). Infiltrating monocyte-derived macrophages secrete inflammatory mediators such as oxygen radicals, which contribute to axonal demyelination and damage, resulting in neurological deficits. Flavonoids are compounds occurring naturally in food, which scavenge oxygen radicals and have antiinflammatory properties. To investigate whether they might suppress clinical symptoms in MS, we treated rats sensitized for acute and chronic experimental allergic encephalomyelitis, an experimental model of MS, with flavonoids. We demonstrated that the flavonoid luteolin substantially suppressed clinical symptoms and prevented relapse when administered either before or after disease onset. Luteolin treatment resulted in reduced inflammation and axonal damage in the CNS by preventing monocyte migration across the brain endothelium. Luteolin influenced migration by modulating the activity of Rho GTPases, signal transducers involved in transendothelial migration. Oral administration of luteolin also significantly reduced clinical symptoms.