SimvaStatin Regulates Oligodendroglial Process Dynamics And Survival
Miron VE, Rajasekharan S, Jarjour AA, Zamvil SS, Kennedy TE, Antel JP
Glia 2007 Jan 15;55(2):130-43
McGill University, NeuroImmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada
SimvaStatin, a lipophilic Statin that crosses the Blood-Brain Barrier, is being evaluated as a potential therapy for Multiple Sclerosis (MS) due to its anti-inflammatory properties.
We assessed the effects of SimvaStatin on cultures of rat newborn and human fetal Oligodendrocyte Progenitor Cells (OPCs).
And, human adult mature Oligodendrocytes (OLGs) with respect to cellular events pertaining to Myelin maintenance and repair.
Short-term SimvaStatin treatment of OPCs (1 day) induced robust process extension, enhanced differentiation to a mature phenotype, and decreased spontaneous migration.
These effects were reversed by Isoprenoid products and mimicked with an inhibitor of Rho kinase (ROCK), the downstream effector of the Isoprenylated protein RhoA GTPase.
Prolonged treatment (2 days) caused process retraction that was rescued by Cholesterol, and increased cell death (4 days) partially rescued by either Cholesterol or Isoprenoid co-treatment.
In comparison, SimvaStatin treatment of human mature OLGs required a longer initial time course (2 days) to induce significant process outgrowth, mimicked by inhibiting ROCK.
Prolonged treatment of mature OLGs was associated with process retraction (6 days) and increased cell death (8 days).
Human-derived OPCs and mature OLGs demonstrated an increased sensitivity to SimvaStatin relative to the rodent cells, responding to nanomolar versus micromolar concentrations.
Our findings indicate the importance of considering the short- and long-term effects of systemic ImmunoModulatory therapies on Neural Cells affected by the MS disease process.
(c) 2006 Wiley-Liss, Inc.
IM Interferon-ß-1a Delays Definite Multiple Sclerosis 5 Years After A First DeMyelinating Event
Kinkel RP, Kollman C, O'Connor P, Murray TJ, Simon J, Arnold D, Bakshi R, Weinstock-Gutman B, Brod S, Cooper J, Duquette P, Eggenberger E, Felton W, Fox R, Freedman M, Galetta S, Goodman A, Guarnaccia J, Hashimoto S, Horowitz S, Javerbaum J, Kasper L, Kaufman M, Kerson L, Mass M, Rammohan K, Reiss M, Rolak L, Rose J, Scott T, Selhorst J, Shin R, Smith C, Stuart W, Thurston S, Wall M
CHAMPIONS Study Group
Neurology 2006 Mar 14;66(5):678-84
The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed:
That IM Interferon-beta-1a (IFN-ß-1a) significantly slows the rate of development of Clinically Definite Multiple Sclerosis (CDMS).
Over 2 years in high-risk patients who experience a first clinical DeMyelinating event.
This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]).
To determine if the benefits of IFN-ß-1a observed in CHAMPS are sustained for up to 5 years.
CHAMPS patients at participating CHAMPIONS sites were enrolled in the study.
All patients were offered, but not required to take, IFN-ß-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization).
Patients who received placebo in CHAMPS were considered the Delayed Treatment DT group.
And patients who received IFN-ß-1a in CHAMPS were considered the Immediate Treatment IT group.
The primary outcome measure was the rate of development of CDMS.
Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years.
Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS.
The median time to initiation of IFN-ß-1a therapy in the DT group was 29 months.
The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03).
Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of Neurologic symptoms.
Few patients in either group developed major disability within 5 years.
These results support the use of IM Interferon-ß-1a after a first clinical DeMyelinating event.
And indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.
Bo L, Geurts JJ, Mork SJ, van der Valk P
Acta Neurol Scand Suppl 2006;183:48-50
VU University Medical Center, Department of Pathology, MS Center, Amsterdam, The Netherlands
Although Multiple Sclerosis (MS) has been considered a White Matter disease, MS lesions are known to occur in Gray Matter.
Recent ImmunoHistoChemical studies have demonstrated extensive Gray Matter DeMyelination in chronic MS.
The most common lesion type consists of purely Cortical lesions extending inward from the surface of the Brain.
This lesion subgroup is grossly underestimated by standard HistoChemical Myelin staining methods.
Some MS patients have SubPial DeMyelinatio in all Cortical areas of the Brain; this pattern has been termed ''general Cortical SubPial DeMyelination''.
Extensive Cortical DeMyelination is associated with the Progressive phases of disease, as less Cortical DeMyelination has been detected in Relapsing/Remitting MS.
The pathology of Gray Matter lesions differs from that of White Matter lesions.
Gray Matter lesions are less inflammatory, with less Macrophage and Lymphocyte infiltration.
In purely Cortical lesions there is no significant increase in Lymphocytes.
Compared with Non-DeMyelinated adjacent Cortical areas in MS patients or Cerebral Cortex in control patients.
Significant Axonal transection and Neuronal loss have been demonstrated in other MS lesions.
Current Magnetic Resonance Imaging (MRI) methods are not sensitive for purely Cortical MS lesions.
The clinical significance of Cortical MS lesions may not be characterized until more sensitive MRI methods are developed.
Distinct Roles Of Protein Kinase R And Toll-Like Receptor 3 In The Activation Of Astrocytes By Viral Stimuli
Carpentier PA, Williams BR, Miller SD
Glia 2007 Feb;55(3):239-52
Northwestern University Institute for NeuroScience, Feinberg School of Medicine, Department of MicroBiology-Immunology, Interdepartmental Immunobiology Center, Northwestern University, Chicago, Illinois
Impaired Immune surveillance and constitutive ImmunoSuppressive properties make the Central Nervous System (CNS) a particular challenge to Immune defense.
And require that CNS-resident cells be capable of rapidly recognizing and responding to infection.
We have previously shown that Astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of Innate Immune functions.
In the current study, we examine the activation of Innate Immune functions of Astrocytes by Theiler's Murine Encephalomyelitis Virus (TMEV).
A PicornaVirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an Autoimmune DeMyelinating Disease that resembles human Multiple Sclerosis.
Astrocytes infected with TMEV are activated to produce Type 1 Interferons, the Cytokine IL-6, and Chemokines CCL2 and CXCL10.
We further examined the mechanisms that are responsible for the activation of Astrocytes in response to direct Viral infection and treatment with poly I:C.
We found that the cytoplasmic dsRNA-activated kinase PKR is important for Innate Immune responses to TMEV infection, but has no role in their induction by poly I:C delivered ExtraCellularly.
In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C.
These results highlight the differences between responses induced by direct, nonlytic Virus infection and ExtraCellular poly I:C.
The activation of Astrocytes through these different pathways has implications for the initiation and progression of Viral Encephalitis and DeMyelinating Diseases such as Multiple Sclerosis.
(c) 2006 Wiley-Liss, Inc.
IL-15 Is Elevated In Serum And CerebroSpinal Fluid Of Patients With Multiple Sclerosis
Rentzos M, Cambouri C, Rombos A, Nikolaou C, Anagnostouli M, Tsoutsou A, Dimitrakopoulos A, Triantafyllou N, Vassilopoulos D
J Neurol Sci 2006 Feb 15;241(1-2):25-9
Aeginition Hospital-Athens Medical School, Department of Neurology, 72-74 Vas.So phias Av, Greece
InterLeukin-15 (IL-15) is a novel ProInflammatory Cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of Multiple Sclerosis.
It is produced by activated blood Monocytes, Macrophages and Glial Cells. There is little information about the involvement of IL-15 in the development of Multiple Sclerosis (MS).
The objective of our study was to measure IL-15 Serum and CerebroSpinal Fluid (CSF) levels in MS patients and to correlate Serum and CSF IL-15 concentrations with clinical parameters of the disease.
CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels.
Materials And Methods
We measured Serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with Inflammatory (IND) and Non-Inflammatory Neurological Diseases (NIND) studied as control groups.
IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease.
MS patients were found to have significantly higher Serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045).
Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003).
Among MS subgroups there were no statistically different IL-15 Serum and CSF concentrations.
No significant correlation of Serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found.
C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients.
Our findings suggest a possible role of IL-15 in the ImmunoPathogenetic mechanisms of MS.
Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D
Clin Neurol NeuroSurg 2006 Sep;108(6):527-31
Aeginition Hospital-Athens Medical School, Department of Neurology, 72-74 Vas.Sophias Av, Greece
PeroxyNitrite (PN) has been implicated in Multiple Sclerosis (MS) and its animal model Experimental Allergic Encephalomyelitis.
Uric Acid (UA) Serum levels of MS patients, a natural scavenger of PN, were found lowered in some recent studies.
The objective of our study was to correlate UA Serum levels and several clinical parameters of MS.
We also tried to investigate Serum UA changes during treatment with ImmunoModulating or ImmunoSuppressing drugs in the last 6 months.
Patients And Methods
We measured UA Serum levels in 190 patients with MS and 58 age and gender matched patients with Inflammatory (IND) and Non-Inflammatory Diseases (NIND) studied as control groups.
UA levels were correlated with clinical parameters as type of the disease, duration, disability, Magnetic Resonance Imaging (MRI) activity and female gender.
In the overall MS group, patients were found to have significantly lower mean Serum Uric Acid levels compared with the IND (p = 0.0029) and the NIND group (p < 0.0001).
UA Serum concentrations were not inversely correlated with duration of the disease (p = 0.87), with disability as assessed by Expanded Disability Status Scale (EDSS) score (p = 0.67) and MRI activity (p = 0.36).
Treatment with ImmunoModulating or ImmunoSuppressing drugs had no influence in UA levels (p = 0.85).
Patients with Clinically Isolated Syndromes (CIS) were found to have significantly lower UA concentrations compared with IND and NIND patients (p = 0.009 and < 0.001, respectively).
Our findings suggest that lower Serum UA levels in MS patients may represent a primary, constitutive loss of protection against Nitric Oxide.
And, the development of CNS inflammation and tissue damage may not have a direct effect to UA Serum levels.
They also provide support that the earlier increase of UA Serum levels might be beneficial in the future treatment of MS.
Motor Assessment Of Upper Extremity Function And Its Relation With Fatigue, Cognitive Function And Quality Of Life In Multiple Sclerosis Patients
Yozbatiran N, Baskurt F, Baskurt Z, Ozakbas S, Idiman E
J Neurol Sci 2006 Jul 15;246(1-2):117-22
Dokuz Eylul University, School of Physical Therapy and Rehabilitation, Izmir, Turkey
The aim of this study was to assess the motor function of upper extremity and its relation with fatigue, cognitive function and quality of life in Multiple Sclerosis (MS) patients.
Design & Setting
Cross-sectional and controlled study. Outpatient clinic in a university hospital.
Thirty-one patients with MS (25 women, 6 men; mean age 39.74 +/- 10.10 years; mean EDSS, 2.56 +/- 1.91) and 30 healthy subjects (20 women, 10 men; mean age 33.56 +/- 8.85 years) were enrolled into the study.
Nine-Hole Peg Test (9-HPT) and Valpar Component Work Sample Test (VCWS-4), Upper Extremity Index (UEI), Paced Auditory Serial Addition Test (PASAT), Fatigue Severity Scale (FSS), and the Multiple Sclerosis Quality of Life-54 (MSQOL-54).
MS patients showed significant impairment in upper extremity motor functions, Cognitive function and excessive Fatigue compared to controls (p < 0.05).
9-HPT in MS group correlated with EDSS, UEI and MSQOL-54 physical health and Cognitive function, whereas VCWS-4 scores (assembly right, assembly left and disassembly) correlated only with EDSS and UEI.
No correlation was found between the VCWS-4 and Cognitive function and Fatigue in both of the groups. Compared to control group, a strong correlation existed between the 9-HPT and VCWS-4 in MS patients (p < 0.05).
The results indicate that disability level (EDSS), UEI and Cognitive function in MS patients are related with impairment in upper extremity motor function.
This again contributes to an impairment in physical domain of quality of life.
A strong correlation of the 9-HPT with VCWS-4 supports the use of the 9-HPT as a measure of manual dexterity and gross motor functions.