salicylates and Paralysis

To evaluate the effects of the synthetic Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid (FTS) on acute and chronic experimental autoimmune encephalomyelitis (EAE and CR-EAE).. Treatment of EAE and MS is based on immunosuppression aiming at downregulation of the proliferating myelin-reactive lymphocytes. One of the pathways of lymphocyte activation involves the GTP-binding protein Ras. FTS destabilizes the attachment of Ras to the cell membrane, resulting in an inhibition of the Ras-mediated signal transduction pathways.. EAE was induced in SJL/J mice by immunization with spinal cord homogenate (MSCH) in adjuvant and two i.v. boosts of pertussis antigen and CR-EAE with passive transfer of proteolipid protein (PLP)-activated lymphocytes. Animals were treated daily starting either from the day of EAE-induction (or cell transfer) or at a later stage, with i.p. injections of FTS (5 mg/kg/day). The clinical severity of the disease was evaluated daily and scored using a 0-6 scale.. In six separate experiments, 27 of the 38 (71.7%) vehicle-treated animals developed clinical signs of EAE compared to 17/38 (44.7%) of the FTS-treated mice (p=0.02, t-test). The maximal average score in the control group was 2.94+/-2.2, whereas in the FTS group it was significantly lower (1.63+/-2.2, p=0.01). Mortality was 26.3% and 10.5% in the two groups, respectively (p=0.03). When treatment was initiated at a later stage, just before the onset of the clinical signs, the protective effect was even more pronounced. A significant suppression of clinical signs was also observed in the CR-EAE model (p=0.02). Lymphocyte proliferation assays demonstrated a more than twofold decrease in the reactivity to myelin antigens (MBP and PLP) and downregulation of the activated lymphocytes (expressing the CD62L, and IA-k-MHC Class I markers and the Vb17 T-cell receptor) in the FTS-treated group; in vitro FTS suppressed the Ras activity of lymphocytes and inhibited the proliferative ability of the lymphocytes in a dose-dependent manner.. FTS suppresses EAE by downregulation of myelin-reactive activated T-lymphocytes. Since FTS did not induce generalized immunosuppressive effects, it may offer significant advantages over the broad immunosuppressive modalities and may be a candidate treatment for autoimmune diseases, such as MS.

Topics: Animals; Antigens, Surface; Cell Division; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Drug Administration Schedule; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Farnesol; Female; Lymphocyte Activation; Lymphocytes; Mice; Myelin Proteins; Myelin Sheath; Paralysis; ras Proteins; Salicylates; Survival Rate; Treatment Outcome

Topics: Anilides; Animals; Behavior, Animal; Body Weight; Brain; Bromine; Chromatography, Gas; Hexachlorophene; Male; Neurologic Manifestations; Organ Size; Paralysis; Pituitary Gland; Prostate; Rats; Reproduction; Salicylamides; Salicylates; Seminal Vesicles; Testis; Time Factors

Topics: Adrenal Cortex Hormones; Biopsy; Child; Child, Preschool; Exophthalmos; Humans; Male; Myositis; Oculomotor Muscles; Ophthalmoplegia; Paralysis; Periostitis; Pupil; Salicylates; Sex Factors

Topics: Acute Kidney Injury; Adult; Benzoates; Burns, Electric; Humans; Malates; Male; Necrosis; Ointments; Paralysis; Peripheral Nervous System Diseases; Radial Nerve; Salicylates

Topics: Adolescent; Adrenal Cortex Hormones; Brain Stem; Encephalitis; Heart Diseases; Humans; Paralysis; Salicylates

Topics: Anabolic Agents; Biochemical Phenomena; Biochemistry; Calcium; Calcium, Dietary; Diet; Edetic Acid; Hyaluronoglucosaminidase; Hydrogen-Ion Concentration; Hypercalcemia; Immobilization; Inositol; Kidney Calculi; Lithiasis; Paralysis; Paraplegia; Pathology; Poliomyelitis; Salicylates; Steroids; Urine

Topics: Humans; Medicine; Paralysis; Poliomyelitis; Salicylates; Salicylic Acid