myelin-basic-protein and Edema

Characteristics of myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE) include acute edema and infiltration of mononuclear cells (MNCs) in the microvessels of central nervous system (CNS). Aquaporin-4 (AQP4) is a water channel protein expressed in astrocytes foot process throughout the CNS. We performed immunostaining, western blotting and semi-quantitative real-time RT-PCR of AQP4 and glial fibrillary acidic protein (GFAP) in CNS from rats immunized with MBP. Immunohistochemical analysis revealed that AQP4 is down-regulated in MNCs infiltrated microvessels of rats with EAE. Furthermore, western blotting and real-time RT-PCR analyses showed that AQP4 was significantly decreased at the stage of severe EAE compared with control rats. On the other hand, expression of GFAP-protein was significantly increased after stage of severe EAE. Our findings suggest that AQP4 may be involved in forming edema in the inflammatory lesions of EAE accompanying with up-regulation of reactive astrocyte.

Topics: Animals; Aquaporin 4; Astrocytes; Central Nervous System; Down-Regulation; Edema; Encephalomyelitis, Autoimmune, Experimental; Female; Glial Fibrillary Acidic Protein; Immunization; Leukocytes, Mononuclear; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spinal Cord

Alterations of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and leakage of serum proteins induce vasogenic edema and cell damage. The possibility that two members of the neurotrophin family, BDNF or IGF-1 induce neuroprotection by attenuating the BSCB permeability following trauma was examined in a rat model. Repeated topical application of BDNF or IGF-1 (0.1 1microg, 0.5 microg or 1 microg in 10 microl) onto the spinal cord 30 min before SCI or 2, 5, 10 or 30 min thereafter significantly attenuated BSCB permeability to Evans blue and iodine. In the neurotrophin treated rats. edema formation, degradation of MBP, and myelin vesiculation were much less frequent compared to the untreated traumatised rats. The protective effect of BDNF and IGF-1 was most pronounced at the high dose (1 microg in 10 microl) given either 30 min before or within 10 min after SCI. The observations suggest that early intervention with neurotrophins in high doses following trauma (within 10 min) attenuates disturbances of the fluid microenvironment of the spinal cord. This indicates that BSCB opening plays an important role in SCI induced myelin vesiculation and cord pathology.

Topics: Animals; Axons; Brain-Derived Neurotrophic Factor; Capillary Permeability; Diffuse Axonal Injury; Edema; Endothelium, Vascular; Insulin-Like Growth Factor I; Male; Microcirculation; Myelin Basic Protein; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Diseases; Spinal Cord Injuries

Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the central nervous system (CNS). It is an animal model of post-infectious encephalomyelitis and multiple sclerosis (MS). Acute EAE is mediated by macrophages and by T helper 1 (Th1) lymphocytes directed against brain antigens. Inflammation in EAE could potentially be modified by prostaglandins (PG) secreted by blood monocytes (Mo) and brain glial cells. PGE elevates cAMP, which inhibits Mo function and selectively blocks secretion of cytokines by Th1 cells. In the present study, we found that a long-acting PGE1 analogue (LAPGE) inhibited clinical and histological EAE. Indomethacin (INDO) also suppressed active EAE. The combination of INDO plus LAPGE inhibited disease further, possibly by allowing LAPGE to function unopposed by immunostimulatory PG. EAE was suppressed when these agents were administered from the time of immunization or from the onset of clinical disease. The combination of INDO plus LAPGE also inhibited delayed-type hypersensitivity (DTH) reactions to myelin basic protein (MBP), and diminished in vitro lymphocyte responses to mitogens and MBP. PGE analogues and modifiers of arachidonate metabolism block autoimmune responses to brain antigens in vitro and in vivo, and may ameliorate inflammatory and autoimmune diseases of the brain and other organs.

Topics: Alprostadil; Animals; Arachidonic Acid; Drug Combinations; Edema; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Indomethacin; Lymphocyte Activation; Misoprostol; Myelin Basic Protein; Prostaglandins; Rats; Rats, Inbred Lew

Experimental allergic neuritis (EAN) was induced in normal and irradiated Lewis rats by passively transferring T cells sensitized to SP-26, a peptide fragment of P2 myelin protein. The recipients became sick 4-8 days post transfer and the degree of disability correlated directly with the dose of T cells. Smaller doses caused demyelination of nerve roots and sciatic nerves and larger doses produced more severe demyelination and significant axonal degeneration. Irradiated recipients developed similar clinical EAN and showed macrophage-mediated demyelination despite severe suppression of the host inflammatory response.

Topics: Animals; Axons; Edema; Female; Immunization; Immunotherapy, Adoptive; Inflammation; Myelin Basic Protein; Myelin P2 Protein; Myelin Sheath; Nerve Degeneration; Neuritis, Autoimmune, Experimental; Peptide Fragments; Rats; Rats, Inbred Lew; Sciatic Nerve; Spinal Nerve Roots; T-Lymphocytes; Time Factors; Whole-Body Irradiation

There is suggestive but inconclusive evidence for a contribution of T cells and antimyelin antibodies to the pathogenesis of the Guillain-Barré polyneuropathy. We have studied the potential synergism of cellular and humoral immunity in the adoptive transfer model of EAN. EAN was induced in Lewis rats by injecting varying doses of P2 peptide (SP26)-sensitized T lymphocytes. Disease severity was dose-dependent. The addition of intravenous GC-AB to a subclinical dose of SP26-sensitized T cells resulted in overt clinical disease and markedly enhanced demyelination. Intravenous injection of antibody alone had no effect. We conclude that activated neuritogenic T cells, while entering into peripheral nerves, alter the blood-nerve barrier, which gives circulating demyelinating antibodies access to the endoneurium. The observations support the concept of a synergistic role of T-cell autoimmunity and humoral responses in the inflammatory demyelination of Lewis rat EAN.

Topics: Animals; Antibodies; Axons; Demyelinating Diseases; Edema; Female; Galactosylceramides; Ganglia, Spinal; Immunization, Passive; Lymphocyte Activation; Macrophages; Male; Motor Neurons; Myelin Basic Protein; Myelin P2 Protein; Nerve Degeneration; Neurilemma; Neuritis, Autoimmune, Experimental; Neurons, Afferent; Rabbits; Rats; Rats, Inbred Lew; Sciatic Nerve; Spinal Cord; Spinal Nerve Roots; T-Lymphocytes

Triethyltin (TET) is a neurotoxicant that produces severe but transient cerebral edema, characterized ultrastructurally by vacuolation of the intraperiod line of central nervous system (CNS) myelin. TET has been reported to depress levels of myelin basic protein (MBP), a protein thought to play a critical role in myelin compaction. In the present study, the genomic expression (i.e., mRNA) of MBP was monitored throughout the pathogenesis of TET-induced myelin edema and recovery in Sprague-Dawley rats given a single injection of a neuropathic (8.0 mg/kg) or non-neuropathic (0.8 mg/kg) dose of TET-bromide. Levels of MBP-mRNA from the anterior and posterior brain were collected 1 hr, 3 hr, 2d, and 7d, postexposure. The optic nerve and caudal brainstem, representing anterior and posterior brain sites, respectively, were examined at the same time-points for ultrastructural evidence of edema and recovery. Our data indicate that neuropathic doses (8.0 mg/kg) of TET significantly stimulated MBP transcript throughout the brain at all exposure time-points. The magnitude and time-course of this stimulation differed in the anterior and posterior brain, with the latter region showing higher levels of MBP-mRNA. In the posterior brain, the highest levels of mRNA correlated with the appearance of edema in the caudal brainstem. In the anterior brain, MBP-mRNA levels were only marginally increased over controls. Ultrastructural evidence of myelin edema was confined to the brainstem in rats treated with neuropathic dose of TET. Intralamellar vacuolation appeared at 3 hr and 2d postexposure and could be correlated with peak levels of MBP transcript, whereas, recompacted myelin, which appeared by 7d postexposure, was associated with declining levels of the mRNA. Ultrastructural changes in the oligodendroglia were suggestive of metabolic stimulation and correlated with high MBP-mRNA levels. In summary, these data indicate that an initial genomic event in TET-induced myelin edema is stimulation of MBP transcript.

Topics: Animals; Blotting, Northern; Central Nervous System Diseases; DNA; DNA Probes; Edema; Male; Myelin Basic Protein; Myelin Sheath; Nucleic Acid Hybridization; Rats; Rats, Inbred Strains; RNA, Messenger; Triethyltin Compounds

The neurological signs induced by injection of tunicamycin are, in young adult rats, virtually identical to those typical of acute experimental autoimmune encephalomyelitis (EAE). Vasogenic exudation, of which the occurrence in the spinal cord of EAE rats has been shown to coincide with the onset of clinical signs, was investigated by quantitative electroimmunoblotting of central nervous system (CNS) tissue at various times following tunicamycin injection of young adult rats. Highly elevated levels of extravasated plasma proteins were observed in the spinal cord from 48 h after injection and, as in EAE rats, these increases coincided with the onset of neurological impairment. At 72 h post-injection, significant increases were also found in the brain of affected animals, albeit at much reduced levels. This is in contrast to previously reported findings in nursling rats where oedema was shown to be predominantly located in the brain. Quantitative electroimmunoblotting for myelin basic protein (MBP) in the CNS of tunicamycin-treated young adult rats indicated that, as in acute EAE, no extensive demyelination had occurred. These data provided further evidence that in both neurological diseases, vasogenic oedema of the spinal cord may be causally related to the appearance of neurological signs and suggested that its differential localization in the CNS may lead to differential neurological impairment.

Topics: Animals; Brain Chemistry; Edema; Encephalomyelitis, Autoimmune, Experimental; Immunoglobulin G; Myelin Basic Protein; Nerve Tissue Proteins; Rats; Serum Albumin; Spinal Cord; Spinal Cord Diseases; Tunicamycin

Light and electron microscope studies were performed on experimental allergic neuritis (EAN) passively induced in Lewis rats by the intravenous injection of T line cells specific for bovine P2 protein. Histologic changes were almost entirely restricted to the peripheral nervous system, being most severe in the sciatic nerve and lumbosacral nerve roots, whereas the brachial nerve and cervical nerve roots were involved to a lesser extent. The lesions were composed of edema, cellular infiltrates, demyelination, and, subsequently, axonal degeneration. Infiltrated macrophages were observed actively stripping the myelin, and the Schwann cell cytoplasm of affected nerve fibers was pushed to the periphery without distinct evidence of degeneration. The first evidence of pathologic change was severe edema in the sciatic nerve 4 days postinoculation. This edema was demonstrated immunohistochemically by the presence of albumin and fibrinogen in the endoneurial space. Mast cell degranulation was observed in these edematous nerve lesions. The cellular infiltrates which formed perivascular cuffs were composed of not only mononuclear cells but also many granulocytes. In the central nervous system, meningeal cell infiltration was also observed in the spinal cord, and after 7 days postinoculation degeneration of the posterior column was also found. This latter observation is thought to represent degeneration due to axonal damage of lumbosacral posterior roots. These pathologic findings in a T cell-mediated model of EAN were essentially the same as those previously reported in conventionally induced EAN or human Guillain-Barré Syndrome. Thus, T cells specific for bovine P2 protein can induce typical EAN lesions in the Lewis rat. The further investigation of this transfer model of EAN will enable us to clarify the pathogenesis of EAN and Guillain-Barré syndrome.

Topics: Animals; Axons; Cell Line; Edema; Female; Humans; Mast Cells; Microscopy, Electron; Myelin Basic Protein; Myelin P2 Protein; Myelin Sheath; Neuritis, Autoimmune, Experimental; Peripheral Nerves; Polyradiculoneuropathy; Rats; Rats, Inbred Lew; T-Lymphocytes

Topics: Animals; Autolysis; Brain; Brain Edema; Central Nervous System; Demyelinating Diseases; Edema; Female; Lipid Metabolism; Myelin Basic Protein; Myelin Proteins; Myelin Sheath; Rats; Spinal Cord; Spinal Cord Diseases; Time Factors; Triethyltin Compounds