dinoprost and Demyelinating-Diseases

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

Oxidative stress plays an important role in multiple sclerosis (MS). Isoprostanes are biomarkers for oxidative stress and have been related to neurological disease progression.. To study whether plasma isoprostane levels were related to disease progression in MS.. Plasma levels of 8,12-iso-iPF2alpha-VI were determined in 17 patients with clinically isolated syndrome (CIS), 41 relapsing-remitting MS (RRMS) patients and 5 primary progressive MS (PPMS) patients and related to MRI and clinical disease parameters.. Isoprostane levels were similar in CIS (60.9, interquartile range (IQR): 47.7-77.7 pg/ml) and RRMS patients (65.3, IQR: 51.9-82.8 pg/ml). The plasma levels were lower in PPMS patients (42.5, IQR: 37.1-49.9) pg/ml, p<0.05) compared to CIS and RRMS patients in this cohort, which was not confirmed in a second cohort. Baseline isoprostane levels were not related to clinical progression defined by conversion form CIS to RRMS or change in Expanded Disability Status Scale (EDSS) or MS Functional Composite (MSFC) scores during six years of follow-up (CIS + RRMS), nor to change in volume of gadolinium enhancing lesions, T2 lesion load or T1 hypointense lesion load during 2.8 years of follow-up (CIS + RRMS).. These results do not support a strong role of 8,12-iso-iPF2alpha-VI in the prediction of disease progression in MS.

Topics: Adult; Biomarkers; Contrast Media; Demyelinating Diseases; Dinoprost; Disability Evaluation; Disease Progression; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Netherlands; Predictive Value of Tests; Prognosis; Time Factors; Up-Regulation

To investigate the expression of cyclo-oxygenases (COX), key enzymes in propagating inflammatory responses by converting arachidonic acid to prostaglandins, in inflammatory demyelinating disorders of the peripheral nervous system (PNS).. Expression and distribution of COX messenger RNA (mRNA) and protein were studied in sural nerve biopsies, serum, and CSF samples from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or, for comparison, with vasculitic neuropathy (VN), which is a inflammatory nondemyelinating disorder, and noninflammatory neuropathies (NIN) using RT-PCR, immunohistochemistry, and immunoblotting. To confirm functional COX-2 activity, the expression of prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) was evaluated by ELISA ex vivo and in vitro.. Whereas COX-1 expression was unaltered in all investigated groups, a significant upregulation of COX-2 mRNA was detected in sural nerves from patients with GBS, CIDP, or VN but not in control subjects with noninflammatory disorders. Macrophages were identified as its primary cellular source. Increased COX-2 protein levels were detectable in serum and CSF from all patients with GBS and, in smaller numbers only, in samples from patients with CIDP or VN but not from the NIN group studied. Moreover, increased levels of PGE(2) and PGF(2alpha) were measurable in sera from patients with GBS, CIDP, or VN and in cell culture supernatants from in vitro stimulated macrophages, indicative of COX-2 activity.. Cyclo-oxygenase-2, expressed by macrophages, may generate prostaglandins during acute inflammatory demyelination of the peripheral nerve.

Topics: Acute Disease; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Demyelinating Diseases; Dinoprost; Dinoprostone; Guillain-Barre Syndrome; Humans; Immunohistochemistry; Inflammation; Isoenzymes; Macrophages; Membrane Proteins; Monocytes; Peripheral Nervous System Diseases; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sural Nerve; Up-Regulation; Vasculitis