endothelin-1 and Optic-Neuritis

Multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system, typically features immune-mediated focal demyelination and secondary axonal degeneration. Cerebral hypoperfusion of the normal-appearing white matter (NAWM) has been reported in MS patients and may be mediated by elevated levels of endothelin-1 (ET-1), a most potent vasoconstrictive peptide released from reactive astrocytes in MS focal lesions. Optic neuritis (ON) is one of the most frequent manifestations of MS and also shows peripapillary vascular hypoperfusion in combination with disc swelling.. We aimed to compare serum and cerebrospinal fluid (CSF) levels of ET-1 as a potential prognostic marker of MS-ON in two groups of patients differing for severity of MS-ON clinical presentation.. A cross-sectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and nonaggressive MS-ON (NA-MS-ON) according to conventional ophthalmological criteria, including optical coherence tomography. CSF and serum concentrations of ET-1 were measured using a commercially available ELISA method.. Sixteen patients consecutively referred to the Units of Neurology for visual disturbances attributable to MS were recruited, 11 (69%) patients with A-MS-ON and 5 (31%) with NA-MS-ON. Median CSF ET-1 levels and CSF/serum ET-1 quotient were significantly higher in patients with A-MS-ON (0.30 vs. 0.56 ng/ml) as compared to NA-MS-ON (0.16 vs. 0.16).. Severity and failure in the recovery from ON in MS patients may depend from vascular hypoperfusion of the optic nerve induced by high intrathecally produced ET-1, a potential prognostic marker of ON recovery in MS. The detection of CSF ET-1 levels may allow identifying groups of ON patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan).

Topics: Adult; Astrocytes; Biomarkers; Cross-Sectional Studies; Endothelin-1; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Optic Nerve; Optic Neuritis; Severity of Illness Index; Tomography, Optical Coherence; White Matter

The endothelins (ETs) cause reactive astrogliosis, which involves neuroinflammation and neurodegeneration in the central nervous system. The purpose of this study was to determine whether blocking the ET signals will protect retinal ganglion cells (RGCs) from optic nerve injury.. We studied the effect of pretreatment with BQ-123, an antagonist of ETA receptors, and BQ-788, an antagonist of ETB receptors, on the survival of RGCs after the optic nerve of rats was crushed. We also performed immunohistological evaluations and real-time PCR of the crushed site to determine the expressions of the ET-1, CD68, GFAP, TNF-α, and iNOS genes in the neuroinflammation of the optic nerves.. The mRNA levels of the ETB receptors were upregulated (5.6-fold) on day 7 after crushing the optic nerves. Cells expressing ETB receptors were recruited mainly to the crushed site where the immunoreactivity to GFAP was weak. These cells were also immuunoreactive to ETs and CD68, a constitutive marker of microglia/macrophages. In the adjacent areas, immunoreactivity to GFAP was intense. Crushing the optic nerve increased the mRNA levels of ET-1 (4.5-fold), CD68 (87.5-fold), GFAP (2-fold), TNF-α (480-fold), and iNOS (6-fold) on day 7. Pretreatment with BQ-788 significantly suppressed the upregulation of these genes and loss of RGCs on day 7, whereas BQ-123 failed to protect the RGCs.. These results suggest that the microglia/macrophages recruited to the crushed site are the possible cellular sources of the ETs, which caused reciprocal activation of astrocytes. Blocking the ETB receptors by BQ-788 rescued RGCs, most likely by attenuating neuroinflammatory events.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Survival; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Macrophages; Male; Microglia; Nerve Crush; Nerve Regeneration; Nitric Oxide Synthase Type II; Oligopeptides; Optic Nerve Injuries; Optic Neuritis; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Receptor, Endothelin B; Retinal Ganglion Cells; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation

Discovery of treatments to protect axonal function of neurons and prevent permanent disability associated with progressive multiple sclerosis (MS) has faced the uphill challenge of assessing relatively small changes in accumulated axon damage within a background environment that is disorganized by CNS inflammation. We hypothesized that transient immunosuppression after initiation of MS-like autoimmune mechanisms would disassociate development of MS-like myelinated axon pathology from development of CNS inflammation in a rat model of autoimmune optic neuritis (AON). A rat model of myelin oligodendrocyte glycoprotein peptide-induced AON was transiently treated (on days 3-7 after antigen exposure) with 5-(4-phenylbutoxy)psoralen (PAP-1), an immunomodulatory drug previously shown specifically to suppress proliferation of effector memory T-cells and immunoglobulin class-switched B-cells. Thirteen days after antigen exposure, optic nerves were harvested for quantitative assessment of 12 MS-associated pathologies using microfluorimetry. With one exception, the immunoreactivities (-ir) for eight markers of MS-like neuroinflammation and immune infiltration were significantly reduced (P < 0.05) by transient PAP-1 treatment, often to levels significantly below those detected in normal control rat optic nerves. With one exception, four immunoreactive markers of MS-like myelinated axon pathology were detected at levels indicating increased axon/myelin pathology compared with vehicle-treated rats with AON (P < 0.05). These data suggest the conclusion that early causative mechanisms in CNS autoimmunity initiate signaling mechanisms that diverge into two separate pathways, one that is strongly associated with inflammatory responses and one that is associated predominantly with disturbed axon-myelin interactions and impaired fast axonal transport.

Topics: Animals; Autoimmune Diseases; Endothelin-1; Female; Ficusin; Inflammation; Interleukin-1; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Optic Neuritis; Pancreatitis-Associated Proteins; Rats; Rats, Inbred BN

Autoimmune optic neuritis is a common early manifestation of multiple sclerosis (MS), yet early therapeutic interventions for MS often have high ocular toxicity associated with increased risks for glaucoma, cataract, or retinopathy. This need to discover better early treatment options prompted our development of a sensitive and reliable means to quantify the broad range of pathologies that potentially develop very early in autoimmune optic neuritis. Tissue microfluorimetry was used to measure seven established markers for human MS pathology in normal and autoimmune optic nerves 13 days after antigen exposure, in a Brown Norway rat model of myelin oligodendrocyte glycoprotein (MOG) peptide (35-55)-induced autoimmune optic neuritis. Optic neuritis rats demonstrated early and significant pathologic changes in five established indices for neuroinflammation, immune infiltration, and demyelination that accurately modeled pathologies characteristic of MS. Two indices of MS-like axon damage advanced significantly within 13 days of antigen exposure. Fluorimetrically measured immunoreactivity (-ir) was significantly decreased for paranodin (PN, the requisite axonal paranodal junction protein) and significantly increased for amyloid precursor protein (APP), indicating loss of paranodal junctions and impaired fast axonal transport, respectively. Measurements showing decreased PN-ir with increased APP-ir quantitatively defined a pattern of early axonal damage in autoimmune optic neuritis.

Topics: Amyloid beta-Protein Precursor; Animals; Axons; Cell Adhesion Molecules, Neuronal; Disease Models, Animal; Endothelin-1; Female; Flow Cytometry; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glycoproteins; Mast Cells; Myelin-Oligodendrocyte Glycoprotein; Optic Neuritis; Peptide Fragments; Rats

The optic neuropathy in multiple sclerosis and glaucoma neuropathy are very common ophthalmological diseases. Multiple sclerosis /MS/ is the chronic inflammatory central nervous system demyelinisation disease with an autoimmunological ethiology. The last investigation of multiple sclerosis indicate the molecular and cellular autoimmunisation aspects. Te role of vasoactive factors is underlines in its pathogenesis which also suggests the common elements of glaucoma and MS pathogenesis. The over expressed vasoconstrictive mechanisms in both diseases can conduct to optic nerve injury. The aim of this study is evaluation of the optic disc morphological changes in sclerosis multiplex patients /MS/ with or without neuritis optica in anamnesis in glaucoma "remodeling" aspects.. We present two patients with coexsist sclerosis multiplex and glaucoma neuropathy, which underwent retrobulbar neuritis.. Coexistance of glaucoma neuropathy and multiple sclerosis neuropathy may indicate common elements of glaucoma and SM pathogenesis. The authors recommend precise morphological optic disc evaluation in multiple sclerosis patients because glaucoma neuropathy may appear.

Topics: Adolescent; Adult; Aged; Endothelin-1; Glaucoma; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Optic Disk; Optic Neuritis; Radiography; Sensitivity and Specificity; Ultrasonography, Doppler, Color; Vasoconstriction; Vasodilation; Vision Disorders; Visual Acuity; Visual Fields