ABSTRACT
OBJECTIVE: The corpus callosum (CC) is commonly affected in multiple sclerosis (MS). The ipsilateral silent period (iSP) is a putative electrophysiological marker of callosal demyelination. The purpose of this study was to re-assess, under recently established optimised protocol conditions [Jung P., Ziemann U. Differences of the ipsilateral silent period in small hand muscles. Muscle Nerve in press.], its diagnostic sensitivity in MS, about which conflicting results were reported in previous studies. METHODS: ISP measurements (onset, duration, and depth) were obtained in the abductor pollicis brevis (APB) muscle of either hand in 49 patients with early relapsing-remitting MS (RRMS) (mean EDSS, 1.3). Standard central motor conduction times to the APB (CMCT(APB)) and tibial anterior muscles (CMCT(TA)), and magnetic resonance images (MRI) were also obtained. RESULTS: ISP measurements showed a similar diagnostic sensitivity (28.6%) as CMCT(APB) (24.5%), while diagnostic sensitivities of CMCT(TA) (69.4%) and MRI of the CC (78.6%) were much higher. Prolongation of iSP duration was the most sensitive single iSP measure. ISP prolongation occurred more frequently when CMCT(APB) to the same hand was also prolonged (40.0% vs. 8.4%, p<0.0001). The correlation between iSP duration and CMCT(APB) was significant (Pearson's r=0.24, p<0.02), suggesting that iSP duration can be contaminated by demyelination of the contralateral corticospinal tract. ISP duration did not correlate with MRI abnormalities of the CC. CONCLUSIONS: ISP measures are neither a sensitive nor a specific marker of callosal conduction abnormality in early RRMS.
Subject(s)
Corpus Callosum/physiopathology , Motor Cortex/physiopathology , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Nerve Fibers, Myelinated/pathology , Neural Conduction/physiology , Adult , Corpus Callosum/pathology , Disease Progression , Early Diagnosis , Electrodiagnosis/methods , Female , Hand/innervation , Hand/physiopathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Muscle, Skeletal/innervation , Muscle, Skeletal/physiopathology , Pyramidal Tracts/physiopathology , Reaction Time/physiology , Transcranial Magnetic Stimulation/methodsABSTRACT
Even though anthralin is a well-established topical therapeutic agent for psoriasis, little is known about its effects and biochemical mechanisms of signal transduction. In contrast to a previous report, we found that anthralin induced time- and concentration-dependent phosphorylation of epidermal growth factor receptor in primary human keratinocytes. Four lines of evidence show that this process is mediated by reactive oxygen species. First, we found that anthralin induces time-dependent generation of H(2)O(2). Second, there is a correlation between a time-dependent increase in anthralin-induced epidermal growth factor receptor phosphorylation and H(2)O(2) generation. Third, the structurally different antioxidants n-propyl gallate and N-acetylcysteine inhibited epidermal growth factor receptor phosphorylation induced by anthralin. Fourth, overexpression of catalase inhibited this process. The epidermal growth factor receptor-specific tyrosine kinase inhibitor PD153035 abrogated anthralin-induced epidermal growth factor receptor phosphorylation and activation of extracellular-regulated kinase 1/2. These findings establish the following sequence of events: (1) H(2)O(2) generation, (2) epidermal growth factor receptor phosphorylation, and (3) extracellular-regulated kinase activation. Our data identify anthralin-induced reactive oxygen species and, more specifically, H(2)O(2) as an important upstream mediator required for ligand-independent epidermal growth factor receptor phosphorylation and downstream signaling.
Subject(s)
Anthralin/pharmacology , Anti-Inflammatory Agents/pharmacology , ErbB Receptors/metabolism , Hydrogen Peroxide/metabolism , Keratinocytes/physiology , Acetylcysteine/pharmacology , Antioxidants/pharmacology , Catalase/genetics , Catalase/metabolism , Cells, Cultured , Electroporation , ErbB Receptors/drug effects , Humans , Keratinocytes/drug effects , Kinetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Phosphotyrosine/metabolism , Psoriasis/drug therapy , Recombinant Proteins/metabolism , Signal TransductionABSTRACT
Among the preventative and protective strategies against the harmful effects of ultraviolet radiation to the skin is the application of antioxidants. Ascorbic acid has been shown to protect against sunburn, delay the onset of skin tumors, and reduce ultraviolet-B-radiation-induced skin wrinkling. In this work, we sought to determine the antioxidative properties of a lipid-soluble derivative of ascorbic acid, ascorbic acid-6-palmitate. We found that ascorbic acid-6-palmitate reduced cellular levels of reactive oxygen species following ultraviolet B irradiation. Treatment of keratinocytes with ascorbic acid-6-palmitate inhibited ultraviolet-B-mediated activation of epidermal growth factor receptor, extracellular regulated kinases 1 and 2, and p38 kinase because of its ability to prevent reduced glutathione depletion and scavenge hydrogen peroxide. Ascorbic acid-6-palmitate strongly promoted ultraviolet-B-induced lipid peroxidation, c-Jun N-terminal kinase activation, and cytotoxicity, however. End products of lipid peroxidation, such as 4-hydroxy-2-nonenal, have been reported to mediate stress-activated protein kinase activation and cell toxicity in epithelial cells. The lipid component of ascorbic acid-6-palmitate probably contributes to the generation of oxidized lipid metabolites that are toxic to epidermal cells. Our data suggest that, despite its antioxidant properties, ascorbic acid-6-palmitate may intensify skin damage following physiologic doses of ultraviolet radiation.