thromboxane-b2 and Multiple-Sclerosis

Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS.

Topics: Adult; Blood Platelets; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Multiple Sclerosis; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

The in vitro effect of methylprednisolone on prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and thromboxane B2 (TXB2) synthesis by adherent monocytes was examined using samples of peripheral blood from 15 patients with multiple sclerosis and 18 normal controls. Eicosanoid production by monocytes was reduced in patients compared with controls and there was a dose-dependent inhibitory effect of methylprednisolone on eicosanoid production in both groups. In vitro production of PGE2 and TXB2 but not LTB4 was reduced in patients with multiple sclerosis following intravenous treatment with methylprednisolone compared with pretreatment samples. In a separate cohort of 20 patients with multiple sclerosis and 15 controls, the in vitro inhibition of PGE2 release by methylprednisolone was not associated with reduced pokeweed-mitogen-stimulated immunoglobulin G synthesis by peripheral blood mononuclear cells. These results suggest that methylprednisolone inhibits monocyte-macrophage function, but this effect is not specific to patients with multiple sclerosis.

Topics: Adult; Cells, Cultured; Dinoprostone; Dose-Response Relationship, Immunologic; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Leukotriene B4; Male; Methylprednisolone; Monocytes; Multiple Sclerosis; Pokeweed Mitogens; Radioimmunoassay; Thromboxane B2

Peripheral blood monocytes have been implicated in the immune reactions that accompany demyelination in patients with multiple sclerosis (MS). We measured prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) release from peripheral monocytes exposed in vitro to complement. Our studies suggest that there is a significantly higher production of PGE2 in monocytes from patients with chronic progressive MS than in those with exacerbation or remitting MS and healthy controls. No significant differences in TxB2 release were noted between the three groups.

Topics: Chromatography, High Pressure Liquid; Complement System Proteins; Dinoprostone; Humans; In Vitro Techniques; Monocytes; Multiple Sclerosis; Prostaglandins; Radioimmunoassay; Thromboxane B2

The aim of this study was to determine the effect of two years of treatment with cyclosporine A on blood pressure and the rates of secretion into the circulation of the vasoconstrictor thromboxane A2 and the vasodilator prostacyclin. Seven patient suffering from multiple sclerosis took part. Their blood pressures and urinary concentrations of 2,3-dinor-thromboxane A2 (a major urinary metabolite of thromboxane A2) and of 2,3-dinor-6-keto-prostaglandin F1 alpha (the major urinary metabolite of prostacyclin) were determined at the end of two years of treatment with cyclosporine A, and once again three months after cessation of this treatment. No other drugs were given during or after cyclosporine A. Mean arterial blood pressure was 113 +/- 5 mmHg (mean +/- SEM) during the cyclosporine A treatment, but fell to 94 +/- 4 mmHg after the three-month's wash-out period. Urinary excretion of the thromboxane metabolite decreased slightly from 674 +/- 150 pg.mg-1 creatinine during cyclosporine A therapy to 503 +/- 90 pg.mg-1-creatinine after the end of therapy. At the same time the prostacyclin metabolite increased significantly from 82 +/- 17 pg.mg-1 creatinine to 113 +/- 23 pg.mg-1 creatinine (P less than 0.05). The ratio of 2,3-dinor-thromboxane B2 to 2,3-dinor-6-keto-prostaglandin F1 alpha (taken as a measure of vasoconstrictor prostanoid activity) fell significantly from 8.4 +/- 0.8 4.7 +/- 0.6 (P less than 0.005). The shift in prostanoid production observed during cyclosporine A treatment could be one causal factor for the hypertensive and thromboembolic events associated with the use of this drug.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cyclosporins; Epoprostenol; Female; Humans; Hypertension; Male; Multiple Sclerosis; Thromboxane A2; Thromboxane B2

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