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1.
J Neurotrauma ; 25(1): 52-61, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18355158

ABSTRACT

UNLABELLED: Neurological complications after mild head injury can include vasogenic edema and/or subsequent development of epilepsy, conditions associated with elevated histamine. In the present study we assessed the potential of mast cells located in the dura mater to contribute to elevated cortical histamine and breakdown of the blood-brain barrier after minor head injury, modeled by either a parietal craniectomy or producing a groove in (scoring) the parietal bone surface to model a grazing head injury. We measured the following effects at 5-20 min after a unilateral parietal craniectomy (rats) or unilateral scoring of the parietal bone (mice): (1) mast cell integrity in subjacent dura mater; (2) subjacent vs. contralateral histamine in dura mater and cerebral cortex; (3) vascular permeability of cerebral cortical blood vessels subjacent to the injury, and; (4) the effects of an H(2)-receptor antagonist on cerebral cortical vascular permeability. RESULTS: Dural mast cells subjacent to the craniectomy became activated (degranulated) concomitant with (1) decreased histamine in dura mater subjacent to the craniectomy; (2) increased histamine in the subjacent cerebral cortex; and (3) extravasation of Evans blue-albumin which stained the subjacent cerebral cortex, indicating a localized breakdown of the blood-brain barrier. Similar results were observed in mice after scoring the parietal bone surface and, additionally, pretreatment with the histamine H(2)-receptor antagonist zolantadine (1 h before injury) dose-dependently inhibited extravasation of Evans blue-albumin. We conclude that even a minor grazing injury of the skull, in the absence of penetrating brain injury or concussion, can activate dural mast cells and elevate cortical histamine, a novel mechanism with potential contributions to neurotraumatic complications arising from a relatively minor or grazing head wound.


Subject(s)
Blood-Brain Barrier/physiopathology , Cerebral Cortex/metabolism , Dura Mater/injuries , Dura Mater/physiopathology , Histamine/metabolism , Mast Cells/metabolism , Skull/injuries , Albumins/pharmacokinetics , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Cerebral Arteries/metabolism , Cerebral Arteries/physiopathology , Cerebral Cortex/blood supply , Cerebral Cortex/physiopathology , Chemotaxis/physiology , Craniocerebral Trauma/metabolism , Craniocerebral Trauma/physiopathology , Craniotomy , Disease Models, Animal , Dose-Response Relationship, Drug , Dura Mater/cytology , Evans Blue/pharmacokinetics , Female , Head Injuries, Closed/metabolism , Head Injuries, Closed/physiopathology , Histamine H2 Antagonists/pharmacology , Mice , Microcirculation/metabolism , Microcirculation/physiopathology , Pia Mater/blood supply , Rats , Rats, Inbred Lew , Secretory Vesicles/metabolism , Up-Regulation/physiology
2.
J Neurosci Res ; 86(9): 2111-24, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18335521

ABSTRACT

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.


Subject(s)
Ficusin/pharmacology , Myelin-Associated Glycoprotein/physiology , Optic Neuritis/immunology , Optic Neuritis/pathology , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Endothelin-1/immunology , Female , Inflammation/immunology , Inflammation/pathology , Interleukin-1/immunology , Myelin Proteins , Myelin-Oligodendrocyte Glycoprotein , Optic Neuritis/classification , Pancreatitis-Associated Proteins , Rats , Rats, Inbred BN
3.
J Neurosci Methods ; 166(2): 217-28, 2007 Nov 30.
Article in English | MEDLINE | ID: mdl-17719649

ABSTRACT

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.


Subject(s)
Axons/pathology , Flow Cytometry/methods , Optic Neuritis/metabolism , Optic Neuritis/pathology , Amyloid beta-Protein Precursor/metabolism , Animals , Axons/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Disease Models, Animal , Endothelin-1/metabolism , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Glial Fibrillary Acidic Protein/metabolism , Glycoproteins , Mast Cells/metabolism , Mast Cells/pathology , Myelin-Oligodendrocyte Glycoprotein , Optic Neuritis/chemically induced , Peptide Fragments , Rats
4.
J Neurosci Res ; 84(8): 1727-37, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17016857

ABSTRACT

Polycystin-1 (PC-1) has been identified as critical to development of the nervous system, but the significance of PC-1 expression in neurons remains undefined, and little is known of its roles outside the kidney, where mutation results in autosomal dominant polycystic kidney disease (ADPKD). In kidney, PC-1 interacts with cadherins, catenins, and its cognate calcium channel polycystin-2 (PC-2), which in turn interacts with a number of actin-regulatory proteins. Because some of the proteins that interact with PC-1 in kidney also participate in synaptic remodeling and plasticity in the hippocampus, we decided to test PC-1's potential to interact with a recently discovered type of plasticity-associated protein (homer 1a/Vesl-1S) in postnatal mouse hippocampus. Homer 1a/Vesl-1S is an activity-induced protein believed to participate in synaptic remodeling/plasticity responses to temporal lobe seizure and learning. Here we report the following. 1) PC-1 contains a homer-binding motif (PPxxF), which lies within its purported cytoplasmic domain. 2) Immunoreactivity for PC-1 (PC-1-ir) is highly colocalized with homer 1a immunoreactivity (H1a-ir) in primary cultured hippocampal neurons. 3) PC-1-ir and H1a-ir are present and appear to be colocalized in mouse hippocampus but not cortex on postnatal day 2 (P2), when higher frequencies of spontaneous activity are normal for hippocampus compared with cortex. 4) An endogenous PC-1-ir band with the correct size for the reported C-terminal G-protein-sensitive domain cleavage product of PC-1 (approximately 150 kDa) coimmunoprecipitates with endogenous homer 1/Vesl-1 proteins from mouse brain, suggesting that PC-1 can interact with homer 1/Vesl-1 proteins in postnatal hippocampal neurons.


Subject(s)
Carrier Proteins/metabolism , Hippocampus/cytology , Neurons/metabolism , TRPP Cation Channels/metabolism , Animals , Animals, Newborn , Blotting, Western/methods , Cells, Cultured , Homer Scaffolding Proteins , Immunohistochemistry/methods , Immunoprecipitation/methods , Mice , Mice, Inbred C57BL , Models, Biological , Neurofilament Proteins/metabolism
5.
J Neurosci Res ; 79(5): 598-607, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15678512

ABSTRACT

Anterograde fast axonal transport (FAxT) maintains synaptic function and provides materials necessary for neuronal survival. Localized changes in FAxT are associated with a variety of central nervous system (CNS) neuropathies, where they may contribute to inappropriate remodeling, a process more appropriately involved in synaptic plasticity and development. In some cases, developmental remodeling is regulated by localized secretion of endothelins (ETs), neuroinflammatory peptides that are also pathologically elevated in cases of neurologic disease, CNS injury, or ischemia. To investigate the potential role of ETs in these processes, we decided to test whether locally elevated endothelin-1 (ET-1) modulates FAxT in adult CNS tissues. We used the established in vivo rat optic nerve model and a novel ex vivo rat hippocampal slice model to test this hypothesis. In vivo, exogenously elevated vitreal ET-1 significantly affected protein composition of FAxT-cargos as well as the abundance and peak delivery times for metabolically-labeled proteins that were transported into the optic nerve. Proteins with molecular weights of 139, 118, 89, 80, 64, 59, 51, 45, 42, 37, and 25 kDa were evaluated at injection-sacrifice intervals (ISIs) of 24, 28, 32, and 36 hr. In acute hippocampal slices maintained on nonvascular supplies of glucose and oxygen, ET-1 significantly decreased the distance traveled along the Schaffer collateral tract by nonmetabolically-labeled lipid rafts at 5 and 10 min after pulse-labeling. In both models, ET-1 significantly affected transport or targeted delivery of FaxT-cargos, suggesting that ET-1 has the potential to modulate FAxT in adult CNS tissues.


Subject(s)
Axonal Transport/drug effects , Endothelin-1/pharmacology , Hippocampus/drug effects , Hippocampus/physiology , Animals , Electrophoresis, Polyacrylamide Gel/methods , Fluorescent Dyes/metabolism , In Vitro Techniques , Male , Mice , Microinjections/methods , Microscopy, Confocal/methods , Models, Animal , Molecular Weight , Neural Networks, Computer , Optic Nerve/drug effects , Optic Nerve/physiology , Organic Chemicals , Radioligand Assay/methods , Rats , Rats, Sprague-Dawley , Time Factors
6.
Invest Ophthalmol Vis Sci ; 43(10): 3223-30, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12356828

ABSTRACT

PURPOSE: Increased levels of endothelins (ETs) are associated with glaucoma and have been said to contribute to the development of glaucomatous optic neuropathy. In glaucoma, movement of selected components of anterograde axonal transport essential in ganglion cell survival is impaired-specifically, the transport of mitochondria. This study evaluates the effect(s) of a single administration of intravitreous ET-1 on anterograde axonal transport in the rat optic nerve. METHODS: Proteins for anterograde axonal transport were pulse labeled by intravitreous injection of (35)S-methionine plus or minus ET-1 (2 nmol) in HEPES buffer (pH 7.4). At appropriate time intervals, optic nerves were dissected, sectioned while frozen, and homogenized in denaturing buffer, and transported protein was quantitated by liquid scintillation counting. Counts corrected for efficiency, quench, background, and decay were statistically evaluated (ANOVA, n = 7). RESULTS: Effects of treatment with intravitreous ET-1 on anterograde axonal transport were significant, biphasic, and prolonged (4 hours to 21 days). The initial phase was a significant enhancement of transport at times normally associated with small, fast-moving tubulovesicles (4 and 24 hours), followed by significant impairments at times normally associated with transport of mitochondria (28-36 hours), cytoplasmic matrix (4 days), and cytoskeletal proteins (21 days). The most pronounced effect of ET-1 was decreased axonal transport at times associated with normal anterograde transport of mitochondrial proteins (28, 32, and 36 hours, P = < 0.001, P < 0.015, and P < 0.001, respectively). This was mimicked by ET-3 at 28 hours. CONCLUSIONS: Effects of intravitreous ET-1 are consistent with a receptor-mediated role for elevated ETs in pathologic misregulation(s) of anterograde axonal transport.


Subject(s)
Axonal Transport/drug effects , Endothelin-1/pharmacology , Optic Nerve/metabolism , Animals , Biological Transport, Active/drug effects , Endothelin-1/administration & dosage , Endothelin-3/pharmacology , Male , Mitochondria/metabolism , Rats , Rats, Sprague-Dawley , Time Factors , Vitreous Body/physiology
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