Zbigniew Stelmasiak

CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis

Objective: To investigate the relationship of CSF and the serum nitric oxide metabolites nitrite and nitrate (NOx) to disease activity and progression in patients with multiple sclerosis (MS). Methods: The study was divided into cross-sectional and follow-up. In the cross-sectional study, 20 patients with relapsing–remitting (RR), 21 with secondary progressive (SP), and 10 with primary progressive (PP) MS and 14 control subjects were included. Patients were assessed on clinical (Expanded Disability Status Scale [EDSS], Ambulation Index [AI], 9-Hole Peg Test [9-HPT]) and MRI measurements. In the follow-up study, 34 MS patients from the cross-sectional study agreed to be assessed again after an average of 3.0 ± 0.5 years. NOx was measured using a vanadium-based assay. Results: In the cross-sectional study, CSF NOx was raised in patients with RR-MS (p = 0.001) and PP-MS (p = 0.02) vs controls. Higher CSF NOx levels were found in patients with mild disability (AI ≤ 6.0; EDSS ≤ 4.0; Multiple Sclerosis Severity Score [MSSS] ≤ 4.8) vs patients with advanced disease (AI > 6.0 [p = 0.002]; EDSS > 4.0 [p = 0.02]; MSSS > 4.8 [p = 0.01]). In the subgroup of patients having Gd-enhancing MRI lesions (n = 11), correlation between the volume of enhancement and CSF NOx was found (r = 0.74, p = 0.01). In the follow-up study, patients with disability progression had higher baseline CSF NOx levels than those who were stable on EDSS (p = 0.02) or AI (p = 0.03). A positive correlation was found between baseline CSF NOx and the change in MR T2-weighted lesion load (r = 0.4, p = 0.03). Conclusions: CSF nitrite and nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI. Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.

Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients

The present study was undertaken to measure cerebrospinal fluid (CSF) levels of kynurenic acid (KYNA) in patients with relapsing-onset multiple sclerosis (MS) during remission or not progressing for at least 2 months. In these patients the levels of CSF KYNA were found to be significantly lower compared with subjects with non-inflammatory neurological diseases, as well as those with inflammatory disease (median (interquartile range): 0.41 (0.3-0.5) pmol/ml, n=26 vs. 0.67 (0.5-1.1), n=23, P<0.01 and 1.7 (1.5-2.6), n=16, P<0.001, respectively). These results provide further evidence of the alterations in the kynurenine pathway during remitting-onset MS.

Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis.

Objectives – Excitotoxicity may play a role in neurodegeneration in amyotrophic lateral sclerosis (ALS). Kynurenic acid (KYNA), an endogenous antagonist of excitatory amino acid receptors, may inhibit excitotoxic lesions. The aim of this study was to determine the concentration of KYNA in ALS patients.

Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine.

Objective – Chemokines are involved in the pathogenesis of multiple sclerosis. The aim of the study was to evaluate the effects of immunosuppressive therapy on production of two proinflammatory chemokines – interleukin‐8 (IL‐8) and RANTES (regulated on activation, normal T cell expressed and secreted).

Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis

This study investigated the cerebrospinal fluid (CSF) levels of ferritin, S100B as biomarkers for glial activation and NfHSM135 — a biomarker of axonal damage — in relation to nitric oxide (NO) metabolites: nitrate and nitrite (NOx) during acute multiple sclerosis (MS) relapse. Thirty-four relapsing—remitting MS (RR-MS) patients during acute relapse and 12 controls were enrolled. Patients were assessed on Expanded Disability Status Scale (EDSS) and underwent lumbar puncture within two weeks following relapse. Twenty patients were available for further follow-up and were assessed on EDSS 6—8 weeks since the relapse onset. The CSF NOx (P < 0.0001), NfHSM135 ( P = 0.01) and S100B (P = 0.009) but not ferritin (P > 0.05) were significantly raised in MS group. There was a significant correlation between CSF ferritin and S100B in RR-MS group (P = 0.004). CSF NOx did not correlate with S100B and ferritin in study groups. RR-MS patients with detectable NfHSM135 levels had higher NOx compared with subjects having undetectable NfHSM135 (P = 0.03). In the follow-up study, raised baseline levels of NOx (P = 0.016) or NfHSM135 (P = 0.04) inversely correlated with the clinical recovery grade expressed as relative EDSS change between baseline and follow-up. In conclusion, NO metabolites were increased and because of their correlation with a biomarker of axonal degeneration (neurofilaments) and a measure for clinical disability (EDSS), relapse-related nitrosative stress is likely to be relevant to the development of sustained disability in an individual patient. Multiple Sclerosis 2008; 14: 59—66. http://msj.sagepub.com

Influence of vitamin C on markers of oxidative stress in the earliest period of ischemic stroke

Experimental studies have demonstrated that oxidative stress plays an essential role in the pathophysiology of ischemic stroke. The objective of the present study was to assess some serum markers of oxidative stress in patients in the early period of ischemic stroke and determine whether vitamin C supplementation affects the parameters of oxidative stress and the clinical status of patients. The study included 60 patients with ischemic stroke and 20 controls. Patients with ischemic stroke were divided into two groups: group I (n = 30), which did not receive vitamin C therapy, and group II (n = 30), which received vitamin C (500 mg/day, i.v.) for 10 days beginning on day 1 after ischemic stroke. Blood levels of bilirubin, creatinine, uric acid and total antioxidative capacity (TAC) were measured on stroke-days 1, 3, 5, and 10. Moreover, the neurological status of patients was evaluated on the same days using the NIHSS, Rankin and Bartel scales. Neurological status was also assessed with the Rankin scale after 3 months. Uric acid and TAC were decreased in group I on all measurement days. However, we did not observe any differences in the clinical status of patients receiving vitamin C during the first ten days of stroke or after 3 months. Although administration of vitamin C (500 mg/day, iv) to ischemic stroke patients since the first day ischemic stroke resulted in elevated serum levels of antioxidants, it did not substantially improve the clinical and functional status of patients after 3 months.

Paraoxonase 1 activity in different types of multiple sclerosis

Background Paraoxonase 1 (PON1) is an antioxidant enzyme bound to plasma high-density lipoproteins and is also present in the brain. Objective The aim of this study was to estimate the activity of PON1 in patients with different types of MS. Methods The PON1 activity toward paraoxon and phenyl acetate and lipid profile was examined in 40 relapsing-remitting (RR) patients in relapse, in 42 RR patients in remission, in 55 progressive MS patients and in 40 healthy individuals. Results PON1 activity did not differ in MS patients compared to control group. PON1 activity in relapse was significantly lower in comparison to the other MS groups. Hypercholesterolemia was observed in MS patients. Conclusion PON1 activity does not change in the course of stable and progressive type of MS and is decreased by the relapse of MS.

Immunomodulatory effects of vitamin D on monocyte-derived dendritic cells in multiple sclerosis

In order to evaluate the effects of vitamin D3 on monocyte-derived dendritic cells (DCs) of relapsing—remitting multiple sclerosis patients, DCs differentiation and maturation were evaluated in vitro based on surface phenotypic changes. The expression of CD14, CD83, CD1a, CD80, CD86, CD206 and C209 was analysed by fluorescence-activated cell sorting. The results reveal that vitamin D3 inhibits both the differentiation and maturation of DCs. Moreover, inhibits the secretion of IL 23/12p40 and increases the secretion of CCL2. The data suggest that one of the mechanisms of the beneficial action of vitamin D3 in multiple sclerosis may be associated with its influence on DCs.

Astrocytic activation in relation to inflammatory markers during clinical exacerbation of relapsing-remitting multiple sclerosis

SummaryThe study aimed to assay the cerebrospinal fluid (CSF) levels of protein S100B, a biomarker of astrocyte activation in relation to kynurenic acid (KYNA) and nitric oxide (NO) metabolites, nitrate/nitrite (NOx) concentrations in acute relapse multiple sclerosis (MS) patients. Twenty relapsing-remitting MS (RR-MS) patients and 10 controls were enrolled. RR-MS patients were assessed on the expanded disability status scale (EDSS) and underwent lumbar puncture. The CSF KYNA, NOx and S100B levels were significantly higher in RR-MS group compared to controls (p = 0.01, 0.001, 0.04, respectively). There was a significant correlation between CSF S100B and KYNA (p = 0.01) but not NOx (p > 0.05) in RR-MS. CSF KYNA, NOx or S100B concentrations did not correlate with disease characteristics of MS patients.Our study suggests the activation of the kynurenine pathway leading to the increase of neuroprotective KYNA in the CSF of MS patients during acute relapse what contrasts with chronic phases of the disease.

Interleukin‐1β converting enzyme/Caspase‐1 (ICE/Caspase‐1) and soluble APO‐1/Fas/CD 95 receptor in amyotrophic lateral sclerosis patients

Objectives – The aim of the study was to investigate the role of ICE/ Caspase‐1 and soluble APO‐1/Fas/CD 95 receptor in amyotrophic lateral sclerosis patients. Material and methods– The apoptosis parameters were measured by enzyme‐linked immunosorbent assay (ELISA) in serum and cerebrospinal fluid from 25 amyotrophic lateral sclerosis and 15 control patients. Results– There has been shown a significant increase of ICE/Caspase‐1 level in serum, and significant decrease of this parameter in cerebrospinal fluid from amyotrophic lateral sclerosis patients. Soluble APO‐1/Fas/CD 95 level in amyotrophic lateral sclerosis patients did not differ from the control group. There was no significant correlation between clinical status, duration of amyotrophic lateral sclerosis, and levels of ICE/Caspase‐1 and soluble APO‐1/Fas/CD 95. Conclusion– Our study suggests that ICE/Caspase‐1 may play a role in neurodegeneration in ALS. Due to ethical difficulties we cannot include patients suffering from progressive neurological diseases, who are a more appropriate control group for the amyotrophic lateral sclerosis patients. Therefore we are limited in drawing conclusions from the research.