Axonal Metabolic Recovery And Potential NeuroProtective Effect Of Glatiramer Acetate In Relapsing/Remitting Multiple Sclerosis
Khan O, Shen Y, Caon C, Bao F, Ching W, Reznar M, Buccheister A, Hu J, Latif Z, Tselis A, Lisak R
Mult Scler 2005 Dec;11(6):646-51
Wayne State University School of Medicine, Department of Neurology, Multiple Sclerosis Center, Detroit, MI 48201, USA
Glatiramer Acetate (GA) is a disease-modifying therapy for Relapsing/Remitting Multiple Sclerosis (RRMS) with several putative mechanisms of action.
Currently, there is paucity of in vivo human data linking the well-established peripheral Immunologic effects of therapy with GA to its potential effects inside the Central Nervous System (CNS).
Brain proton Magnetic Resonance Spectroscopy (MRS) allows in vivo examination of Axonal integrity by quantifying the resonance intensity of the Neuronal marker N-AcetylAspartate (NAA).
In a pilot study to investigate the effect of GA on Axonal injury, we performed combined Brain Magnetic Resonance Imaging (MRI) and MRS studies in 18 treatment naive RRMS patients initiating therapy with GA at baseline and annually for two years on therapy.
A small group of four treatment naive RRMS patients, electing to remain untreated, served as controls.
NAA/Cr was measured in a large central Brain volume of interest (VOI) as well as the Normal-Appearing White Matter (NAWM) within the VOI.
After two years, NAA/Cr in the GA-treated group increased significantly by 10.7% in the VOI (2.17 +/- 0.26 versus 1.96 +/- 0.24, P = 0.03) and by 71% in the NAWM (2.23 +/- 0.26 versus 2.08 +/- 0.31, P = 0.04).
In the untreated group, NAA/Cr decreased by 8.9% at two years in the VOI (2.01 +/- 0.16 versus 1.83 +/- 0.21, P = 0.03) and 8.2% in the NAWM (2.07 +/- 0.24 versus 1.90 +/- 0.29, P = 0.03).
Our data shows that treatment with GA leads to Axonal metabolic recovery and protection from sub-lethal Axonal injury. These results support an in situ effect of GA therapy inside the CNS and suggest potential NeuroProtective effects of GA.
CD26+ CD4+ T-Cell Counts And Attack Risk In Interferon-Treated Multiple Sclerosis
Sellebjerg F, Ross C, Koch-Henriksen N, Sorensen PS, Frederiksen JL, Bendtzen K, Sorensen TL
Mult Scler 2005 Dec;11(6):641-5
Copenhagen University Hospital, The MS Clinic, Glostrup, Denmark
Biomarkers that allow the identification of patients with Multiple Sclerosis (MS) with an insufficient response to ImmunoModulatory treatment would be desirable, as currently available treatments are only incompletely efficacious.
Previous studies have shown that the expression of CD25, CD26 and CCR5 on T-Cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during ImmunoModulatory treatment.
In Interferon-ß (IFN-ß)-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26+ CD4+ T-Cell counts above median, and this risk was independent of the risk conferred by Neutralizing Anti-IFN-ß AntiBodies.
CD26+ CD4+ T-Cell counts may identify patients with MS at increased risk of attack during treatment with IFN-ß.
SimvaStatin Affects Cell Motility And Actin CytoSkeleton Distribution Of Microglia
Kuipers HF, Rappert AA, Mommaas AM, Van Haastert ES, Van Der Valk P, Boddeke HW, Biber KP, Van Den Elsen PJ
Glia 2006 Jan 15;53(2):115-23
Leiden University Medical Center, Department of ImmunoHematology and Blood Transfusion, Leiden, The Netherlands
Statin treatment is proposed to be a new potential therapy for Multiple Sclerosis (MS), an Inflammatory DeMyelinating Disease of the Central Nervous System. The effects of Statin treatment on Brain cells, however, are hardly understood.
We therefore evaluated the effects of SimvaStatin treatment on the migratory capacity of Brain Microglial Cells, key elements in the pathogenesis of MS.
It is shown that exposure of human and murine Microglial Cells to SimvaStatin reduced cell surface expression of the Chemokine receptors CCR5 and CXCR3.
In addition, SimvaStatin treatment specifically abolished Chemokine-induced Microglial cell motility, altered actin CytoSkeleton distribution, and led to changes in IntraCellular vesicles.
These data clearly show that SimvaStatin inhibits several Immunological properties of Microglia, which may provide a rationale for Statin treatment in MS.
(c) 2005 Wiley-Liss, Inc.
Glutamate Inhibition In MS: The NeuroProtective Properties Of Riluzole
Killestein J, Kalkers NF, Polman CH
J Neurol Sci 2005 Jun 15;233(1-2):113-5
VU Medical Centre, Department of Neurology, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
In addition to DeMyelination and damage to Oligodendrocytes, Axonal injury and Neuronal cell death are dominating histopathological characteristics of Multiple Sclerosis (MS).
Still little is known about the cause of the damage. ExtraCellular accumulation of Glutamate contributes to excitotoxic injury of Neurons and Glial Cells, suggesting the maintenance of subtoxic ExtraCellular Glutamate levels may be crucial.
Riluzole is a NeuroProtective agent that inhibits the release of Glutamate from Nerve Terminals and modulates Glutamate, i.e., Kainate and NMDA receptors.
It inhibits excitotoxic injury in several experimental models of NeuroDegenerative Disease. We performed a small run-in versus treatment MR-monitored pilot study in 16 Primary/Progressive MS patients.
The results suggest that Riluzole reduces the rate of Cervical Cord atrophy and the development of T1 HypoIntense lesions on Magnetic Resonance Imaging in Primary/Progressive MS. The rate of Brain Atrophy was only slightly decreased.
The results indicate an effect on mechanisms involving lesion evolution and Axonal loss, but no clear effect on new lesion formation. However, the data suffer from several limitations and must be confirmed in future trials.
9-Cis-Retinoic Acid Suppresses Inflammatory Responses Of Microglia And Astrocytes
Xu J, Drew PD
J NeuroImmunol 2006 Feb;171(1-2):135-44
University of Arkansas for Medical Sciences, Department of Neurobiology and Developmental Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
Retinoic Acid (RA) regulates a wide range of biologic process, including inflammation. Previously, RA was shown to inhibit the clinical signs of Experimental Autoimmune Encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS).
The current study investigated the effects of 9-cis-RA on primary mouse Microglia and Astrocytes, two cell types implicated in the pathology of MS and EAE.
The studies demonstrated that 9-cis-RA inhibited the production of Nitric Oxide (NO) as well as the pro-inflammatory Cytokines TNF-, IL-1ß and IL-12 p40 by LPS-stimulated Microglia.
However, this Retinoid had no effect on IL-6 secretion and increased MCP-1 production by LPS-stimulated Microglia. In LPS-stimulated Astrocytes, 9-cis-RA inhibited NO and TNF- production but had not effect on IL-1ß, IL-6 and MCP-1 secretion.
These results suggest that RA modulates EAE, at least in part, by suppressing the production of NO and specific inflammatory Cytokines from activated Glia and suggests that RA might be effective in the treatment of MS.
Arvanil Inhibits T-Lymphocyte Activation And Ameliorates Autoimmune Encephalomyelitis
Malfitano AM, Matarese G, Pisanti S, Grimaldi C, Laezza C, Bisogno T, Di Marzo V, Lechler RI, Bifulco M
J NeuroImmunol 2006 Feb;171(1-2):110-9
Universita' di Salerno, Dipartimento di Scienze Farmaceutiche, Via Ponte don Melillo 84084 Fisciano (Salerno), Italy; Department of Immunology, Hammersmith Campus, Imperial College London, UK
This study examined the ImmunoModulatory effect of Arvanil, a synthetic Capsaicin-Anandamide hybrid. Arvanil inhibits Lymphocyte proliferation and IFN-γ production.
The phenotype of activated CD4+T-Cells treated with Arvanil shows a down-regulation of T-Cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and Anandamide do not induce Apoptosis on CD4+T-Cells.
Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB.
In vivo, Arvanil ameliorates Experimental Autoimmune Encephalomyelitis in the SJL/J mouse.
Our findings have relevance for the use of Arvanil and related compounds as a novel ImmunoTherapeutic approach in the treatment of Multiple Sclerosis.
Investigating The Presence Of Human HerpesVirus 7 And 8 In Multiple Sclerosis And Normal Control Brain Tissue
Opsahl ML, Kennedy PG
J Neurol Sci 2006 Jan 15;240(1-2):37-44
University of Glasgow Department of Neurology, Division of Clinical Neurosciences, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, Scotland, UK
Multiple Sclerosis (MS) is an important DeMyelinating disease of the Central Nervous System, the Etiology of which is thought to have a possible Viral component.
In this study we investigated the possible involvement in MS of two Herpes Viruses: the NeuroTropic Human HerpesVirus 7 (HHV-7) and the related Human HerpesVirus 8 (HHV-8).
Utilizing Fluorescent In Situ Hybridisation (FISH) techniques, we examined human post mortem tissues for the presence of immediate early and late Viral gene or protein expression in MS patient Normal-Appearing White Matter (NAWM), lesional tissue and normal control Brain samples.
HHV-7 and/or HHV-8 mRNA or protein was detected in some individuals in all three sample categories and was restricted to Oligodendrocytes, as determined by double mRNA FISH analysis or Immuno fluorescence (IF).
No samples showed evidence of Viral mRNA when subjected to RT-PCR on extracted Ribonucleic Acid. We therefore conclude that there is little evidence in our particular sample cohort to suggest involvement of either HHV-7 or HHV-8 in MS.