silicon and Multiple-Sclerosis

Cannabinoids are widely studied as therapeutic agents for the treatment of various diseases. Among them, THC and CBD are two important phytocannabinoids which have served as structural templates for the design of synthetic analogs. In this study, we designed and synthesized a variety of novel cannabinoids based on the structural backbones of THC and CBD using the carbon-silicon switch strategy. A dimethyl silyl group was introduced as the tail group and two series of novel compounds were designed and synthesized, which showed a wide range of binding affinity for CB1 and CB2 receptors. Among them, compound 15b was identified as a non-selective CB1 and CB2 agonist and 38b as a selective agonist for the CB2 receptor. Preliminary screening showed that both compounds have improved metabolic stability than their carbon analogs and good in vivo pharmacokinetic profiles. Furthermore, both 15b and 38b significantly alleviated the phenotype of experimental autoimmune encephalomyelitis (EAE) in mice.

Topics: Animals; Cannabinoids; Carbon; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Encephalomyelitis, Autoimmune, Experimental; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Multiple Sclerosis; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Silicon; Structure-Activity Relationship

Removal of chondroitin sulfate proteoglycans (CSPGs) with chondroitinase ABC I (ChABC) facilitates axonal plasticity, axonal regeneration and remyelination, following injury to the central nervous system (CNS). However, the ChABC rapidly undergoes thermal inactivity and needs to be injected repeatedly. Here this limitation was overcame by immobilizing the ChABC on porous silicon (PSi) nanoparticles (ChABC@PSi). The efficacy of immobilized ChABC on CSPGs level and the demyelination insult was assessed in mice corpora callosa demyelinated by 6 weeks cuprizone (CPZ) feeding. ChABC@PSi was able to reduce the amount of CSPGs two weeks after animals treatment. CSPGs digestion by ChABC@PSi reduced the extent of demyelinated area as well as the astrogliosis. Furthermore, ChABC@PSi treatment increased the number of newly generated oligodendrocyte lineage cells which imply for enhanced myelin repair. Our results showed that effective CSPGs digestion by ChABC@PSi enhanced remyelination in CPZ model. Accordingly, ChABC@PSi may have a great potential to be used for treatment of diseases like multiple sclerosis and spinal cord injury by promoting the regeneration of damaged nerves.

Topics: Animals; Chondroitin ABC Lyase; Disease Models, Animal; Enzymes, Immobilized; Humans; Male; Mice; Multiple Sclerosis; Myelin Sheath; Nanoparticles; Silicon

Although some studies suggested a link between exposure to trace elements and development of multiple sclerosis (MS), clear information on their role in the aetiology of MS is still lacking. In this study the concentrations of Al, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Sb, Si, Sn, Sr, Tl, V, W, Zn and Zr were determined in the blood of 60 patients with MS and 60 controls. Quantifications were performed by inductively coupled plasma (ICP) atomic emission spectrometry and sector field ICP mass spectrometry. When the two groups were compared, an increased level of Co, Cu and Ni and a decrement of Be, Fe, Hg, Mg, Mo, Pb and Zn in blood of patients were observed. In addition, the discriminant analysis pointed out that Cu, Be, Hg, Co and Mo were able to discriminate between MS patients and controls (92.5% of cases correctly classified).

Topics: Adult; Biomarkers; Discriminant Analysis; Female; Humans; Male; Mass Spectrometry; Metals; Middle Aged; Multiple Sclerosis; Silicon; Specimen Handling; Trace Elements

Twenty-six chemical elements and oxidative status were determined in serum of 12 patients with first demyelinating episode and brain magnetic resonance imaging compatible with the disease at different time points. Quantifications of Al, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Sb, Si, Sn, Sr, V, Tl, W, Zn and Zr, as well as of serum oxidative status and antioxidant capacity were carried out. The results were compared with values obtained from healthy subjects living in the same geographic area. Concentration variability, expressed as coefficient of variation (CV), was evaluated over a six months longitudinal follow-up. The CV was higher for Li and Pb, while showed minimal variation for Ca, Cu, Mg and Zn--elements strictly body regulated. Significant difference (p < or = 0.05) in mean concentrations of Ba, Ca, Cd, Cr, Li, Mn, Mo, Ni, Sb, Si, Sn and Zr between patients at time 0 and controls was also found.

Topics: Adult; Antioxidants; Cohort Studies; Demyelinating Diseases; Female; Follow-Up Studies; Humans; Male; Mass Spectrometry; Metals; Multiple Sclerosis; Oxidants; Oxidative Stress; Silicon