dinoprost and Multiple-Sclerosis

Isoprostanes are prostaglandin-like compounds which are formed by free radical catalysed peroxidation of arachidonic acid esterified in membrane phospholipids. They are emerging as a new class of sensitive, specific and reliable markers of in vivo lipid peroxidation and oxidative damage. Since their initial description of in 1990, the rapid development of analytical methods for isoprostane measurement has allowed to overcome some of the pitfalls of the previous and most widely used methods of assessing free radical injury. Here, we summarise the current knowledge on these novel class lipid peroxidation products and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases. Although the literature data are still not abundant, they indicate that in vivo or post mortem cerebrospinal fluid and brain tissue levels of isoprostane are increased in some diseases such as multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease.

Topics: Alzheimer Disease; Animals; Brain; Dinoprost; Humans; Huntington Disease; Lipid Peroxidation; Multiple Sclerosis; Neurodegenerative Diseases; Oxidative Stress; Prostaglandin-Endoperoxide Synthases

Lipid peroxidation due to oxidative stress (OS) may play an important role in the pathogenesis of chronic systemic inflammatory diseases such as multiple sclerosis (MS). Telomeres, repeated sequences that cap chromosome ends, undergo shortening with each cycle of cell division, resulting in cellular senescence. Research regarding telomere shortening has provided novel insight into the pathogenesis of various diseases. We hypothesized that OS damage leads to inflammatory reactions, which subsequently shortens the telomere length in MS. We enrolled 59 patients with MS, and age- and gender-matched 60 healthy controls. We divided MS subjects into three groups matched for age and gender according to the severity of disability: relatively benign course (BMS), secondary progressive MS, and primary progressive MS (PPMS). We analyzed the telomere length in peripheral blood mononuclear cells and the 8-iso-PGF2α concentration in urine, a reliable and stable marker of lipid peroxidation in vivo. The data showed significant higher levels of urinary 8-iso-PGF2α in MS subjects than in the controls. The lag-time, which represents the direct measurement of the resistance of low-density lipoprotein to oxidation, was shorter in the PPMS subjects than in the groups. Compared to that observed in the controls, the mean telomere length was significantly shorter in the PPMS group, whereas no significant telomere shortening was found between the controls and other subjects. Our data suggest that a decreased telomere length and enhanced lipid peroxidation reflects the severest stage of MS.

Topics: Adult; Dinoprost; Female; Humans; Leukocytes, Mononuclear; Lipid Peroxidation; Male; Middle Aged; Multiple Sclerosis; Oxidative Stress; Telomere Shortening

Previously, we have demonstrated that prostamide/PGF synthase, which catalyzes the reduction of prostaglandin (PG) H2 to PGF2α, is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF2α has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF2α/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, glial activation, and TNFα expression in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF2α/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis.

Topics: Animals; Corpus Callosum; Cuprizone; Demyelinating Diseases; Dinoprost; Disease Models, Animal; Humans; Mice; Motor Activity; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Prostaglandin H2; Receptors, Prostaglandin; Tumor Necrosis Factor-alpha

The CSF level of the isoprostane 8-epi-prostaglandin (PG)-F2alpha (a reliable marker of oxidative stress in vivo) was three times higher in subjects with definite MS than in a benchmark group of subjects with other neurologic diseases. This increase was not correlated with that of PGE2 levels, measured as an index of cyclooxygenase activity, and was much lower in steroid-treated patients. The levels of 8-epi-PGF2alpha were moderately correlated with the degree of disability.

Topics: Adult; Aged; Dinoprost; Dinoprostone; Disabled Persons; F2-Isoprostanes; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Osmolar Concentration; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Reference Values

Levels of PGE, PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane (TXB2) in spinal cords and cerebellums of guinea pigs at different stages of chronic relapsing allergic encephalomyelitis (CREAE) were compared with those in Freund's adjuvant-treated, age-matched controls. PGE and TXB2 levels were found to be increased in spinal cords during acute and relapse phases of the disease. The number of lesions in the spinal cord was similarly increased in acute and relapse stages. There was, however, no similar correlation between number of lesions and eicosanoid levels in the cerebellum with the clinical stages of the disease based on hind limb paralysis. In the acute phase and remission lesion numbers were low, and high levels, similar to those found in the spinal cord, were only found in the relapse phase. Eicosanoid levels were high in the acute phase and remission, and generally low in relapse. The spinal cord levels of eicosanoids in remission and relapse correlated well with previous data obtained from the CSF of patients with multiple sclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Central Nervous System; Cerebellum; Dinoprost; Encephalomyelitis, Autoimmune, Experimental; Guinea Pigs; Humans; Multiple Sclerosis; Prostaglandins; Prostaglandins E; Prostaglandins F; Spinal Cord; Thromboxane B2

Radioimmunoassay (RIA) techniques have been employed to determine prostaglandin (PG) levels in the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients in remission and relapse and in subjects with other neurological diseases (OND). PGE and PGF2 alpha concentrations in spinal fluid from MS patients in relapse were significantly lower than values estimated during remission and in individuals with OND of the central nervous system (CNS). These observations are discussed in relation to the clinical state of patients with demyelinating disease together with a consideration of the concept that disordered immune mechanisms contribute a central role in the pathogenesis of MS.

Topics: Dinoprost; Humans; Leukocyte Count; Multiple Sclerosis; Prostaglandins; Prostaglandins E; Prostaglandins F; Recurrence