Summary
The possibility that serotonin can take part in the initiation of the increased microvascular permeability occurring in a spinal cord trauma was investigated in a rat model with 131I-sodium and lanthanum as tracers. We influenced the serotonin content in the tissue pharmacologically by treating animals with a serotonin synthesis inhibitor, p-chlorophenylalanine (p-CPA), before the production of the injury and compared the results with injured, untreated controls. A small incision was made in the dorsal horn of the lower thoracic cord. It caused a progressive extravasation of 131I-sodium in the damaged segment, measured after 1,2 and 5 h. Rostral and caudal segments also showed a significant but lower accumulation of 131I-sodium. Lanthanum added to the fixative was used as an ionic tracer detectable by electron microscopy. The endothelial cells of microvessels removed from the perifocal region after 5 h showed a marked increase in the number of lanthanum-filled vesicles. Many endothelial cells had a diffuse penetration of the tracer into the cytoplasm and the basement membrane. However, the tight junctions usually remained closed to lanthanum. Pretreatment with p-CPA markedly reduced the extravasation of 131I-sodium measured at 5 h in the traumatized cord. At the cellular level, the endothelial vesicles filled with lanthanum approached the condition of uninjured animals. The diffuse infiltration of lanthanum into endothelial cells and its spread into the basement membrane of the vascular wall were usually absent. Our results indicate that serotonin plays a role in the initiation of the increased microvascular permeability which occurs in spinal cord injuries.
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References
Alexander GL, Kopeloff LM, Alexander RB (1988) Low serotonin turnover in cerebral hemispheres of rats primed with p-chlorophenylalanine. Biogen Amin 5:17–24
Andén NE (1974) Effect of acute axotomy (spinal cord transection) on the turnover of 5-hydroxytryptamine. Adv Biochem Psychopharmacol 10:35–43
Andén NE, Modigh K (1972) Effects of p-chlorophenylalanine and a monoamine oxidase inhibitor on the 5-hydroxytryptamine in the spinal cord after transection. J Neurol Transm 33:211–222
Andén NE, Fuxe K, Hökfelt T (1966) The importance of the nervous impulse flow for the depletion of the monoamines from central neurones by some drugs. J Pharm Pharmacol 18:630–632
Anderson EG (1983) The serotonin system of the spinal cord. In: Davidoff RA (ed) Handbook of the spinal cord, vol 1, pp 241–174
Balentine JD (1978) Pathology of experimental spinal cord trauma. II: Ultrastructure of axons and myelin. Lab Invest 39:254–266
Balentine JD (1988) Spinal cord trauma: in search of the meaning of granular axoplasm and vesicular myelin. J Neuropathol Exp Neurol 47:77–92
Banik NL, Hogan ED, Hsu CY (1987) The multimolecular cascade of spinal cord injury. Studies on prostanoids, calcium, and proteinases. Neurochem Pathol 7:57–77
Barchas J, Usdin E (1977) Serotonin and behaviour. Academic Press, New York, pp 1–177
Beggs JL, Waggener JD (1976) Transendothelial vesicular transport of protein following compression injury to the spinal cord. Lab Invest 34:428–439
Bottaro D, Shepro D, Peterson S, Hechtmann HB (1986) Serotonin, norepinephrine, and histamine mediation of endothelial cell barrier function in vitro. J Cell Physiol 128:189–194
Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677
Bundgaard M (1982) Ultrastructure of frog cerebral and pial microvessels and their impermeability to lanthanum ions. Brain Res 241:57–65
Carbonell AL, Boya J (1988) Ultrastructural study on meningeal regeneration and meningo-glial relationships after cerebral stab wound in the adult rat. Brain Res 439:377–344
Castel M, Sahar A, Erlij D (1974) The movement of lanthanum across diffusion barriers in the choroid plexus of the cat. Brain Res 67:171–184
Costa E, Gessa GL, Sandler M (1974) Serotonin: new vistas. Histochemistry and pharmacology. Adv Biochem Psychopharmacol 10:22–43
de La Torre JC (1981) Spinal cord injury. Review of basic and applied research. Spine 6:315–335
Demediuk P, Sauders RD, Anderson DK, Means ED, Horrocks LA (1987) Early membrane lipid changes in laminectomized and traumatized cat spinal cord. Neurochem Pathol 7:79–89
Demopoulos HB, Flamm ES, Seligman ML, Pietronigro DD, Tomasula J, DeVrescito V (1982) Further studies on free radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury. Can J Physiol Pharmacol 60:1415–1424
Dey PK, Sharma HS (1983) Ambient temperature and development of brain edema in anesthetized animals. Indian J Med Res 77:554–563
Dey PK, Sharma HS (1984) Influence of ambient temperature and drug treatments on brain edema induced by impact injury on skull in rat. Indian J Physiol Pharmacol 28:177–186
Dietrich WD, Watson BD, Busto R, Ginsberg MD, Bethea JR (1987) Photochemically induced cerebral infarction. I. Early microvascular alterations. Acta Neuropathol (Berl) 72:315–325
Doggenweiler CF, Frenk S (1965) Staining properties of lanthanum on cell membranes. Proc Natl Acad Sci USA 53:425–430
Edvinsson L, MacKenzie ET (1977) Amine mechanisms in the cerebral circulation. Pharmacol Rev 28:275–348
Elliott KAC, Jasper H (1949) Measurement of experimentally induced brain swelling and shrinkage. Am J Physiol 157:122–129
Essman W (1978) Serotonin in health and disease. The Central Nervous System, vol 3. Spectrum Publications, New York, pp 1–420
Faden AI (1987) Pharmacotherapy in spinal cord injury: a critical review of recent developments. Clin Neuropharmacol 10:193–204
Faden AI, Gannon A, Basbaum AI (1988) Use of serotonin immunocytochemistry as a marker of injury severity after experimental spinal trauma in rats. Brain Res 450:94–100
Goodman JH, Bingham WG Jr, Hunt WE (1976) Ultrastructural blood-brain barrier alterations and edema formation in acute spinal cord trauma. J Neurosurg 44:418–424
Griffiths IR, Miller R (1974) Vascular permeability to protein and vasogenic edema in experimental concussive injuries to the canine spinal cord. J Neurol Sci 22:291–304
Hall SM, Williams PL (1971) The distribution of electrondense tracers in peripheral nerve fibres. J Cell Sci 8:541–555
Hsu CY, Hogan EL, Gadsden RH Sr, Spicer KM, Shi MP, Cox RD (1985) Vascular permeability in experimental spinal cord injury. J Neurol Sci 70:275–282
Hsu CY, Halushka PV, Hogan EL, Cox RD (1986) Increased thromboxane level in experimental spinal cord injury. J Neurol Sci 74:289–296
Hsu CY, Halushka PV, Spicer KM, Hogan EL, Martin HF (1988) Temporal profile of thromboxane-prostacyclin imbalance in experimental spinal cord injury. J Neurol Sci 83:55–62
Haydon PG, McCobb DP, Kater SB (1984) Serotonin selectively inhibits growth cone motility and synaptogenesis of specific identified neurones. Science 226:561–564
Jellinger K (1972) Traumatic vascular disease of the spinal cord. Handb Clin Neurol 12:556–630
Johansson B (1981) Indomethacin and cerebrovascular permeability to albumin in acute hypertension and cerebral embolism in the rat. Exp Brain Res 42:331–336
Joo F (1987) A unifying concept on the pathogenesis of brain oedemas. Neuropathol Appl Neurobiol 13:161–176
Julius D, MacDermott AB, Axel R, Jessel TM (1988) Molecular characterization of functional cDNA encoding the serotonin 1c receptor. Science 241:558–564
Koe BK, Weissman A (1966) p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516
MacKenzie ML, Shorer Z, Ghabriel MN, Allt G (1984) Myelinated nerve fibres and the fate of lanthanum tracer: an in vivo study. J Anat 138:1–14
MacKenzie ML, Ghabriel MN, Allt G (1984) Nodes of Ranvier and Schmidt-Lanterman incisures: an in vivo lanthanum tracer study. J Neurocytol 13:1043–1055
MacKenzie ML, Ghabriel MN, Allt G (1987) The bloodnerve barrier: an in vivo lanthanum tracer study. J Anat 154:27–37
Means ED, Anderson DK (1987) The pathophysiology of acute spinal cord injury. In: Davidoff RA (ed) Handbook of the spinal cord, vol 5. Marcel Dekker, New York, pp 19–61
Martinez AJ, Alderman JL, Kagan RS, Osterholm JL (1981) Spatial distribution of edema in the cat spinal cord after impact injury. Neurosurgery 8:450–453
Nag S, Robertson DM, Dinsdale HB (1982) Intracerebral arteriolar permeability to lanthanum. Am J Pathol 107: 336–341
Nemecek S, Petr R, Sube P, Rozseval V, Melka O (1977) Longitudinal extension of edema in experimental spinal cord injury: evidence for two types of post-traumatic edema. Acta Neurochir (Wien) 37:7–16
Noble LJ, Wrathall JR (1987) The blood-spinal cord barrier after injury: pattern of vascular events proximal and distal to a transection in the rat. Brain Res 424:177–188
Noble LJ, Wrathall JR (1988) Blood-spinal cord barrier disruption proximal to a spinal cord transection in the rat: time course and pathways associated with protein leakage. Exp Neurol 99:567–578
Pappius HM, Dadoun R (1987) Effects of injury on the indoleamines in cerebral cortex. J Neurochem 49:321–325
Pappius HM, Dadoun R, McHugh M (1988) The effect of p-chlorophenylalanine on cerebral metabolism and biogenic amine content of traumatized brain. J Cereb Blood Flow Metab 8:324–443
Rapoport SI (1976) Blood-brain-barrier in physiology and medicine. Raven Press, New York, pp 1–327
Revel JP, Hamilton DW (1969) The double nature of the intermediate dense line in peripheral nerve myelin. Anat Rec 163:7–16
Revel JP, Karnovsky MJ (1967) Hexagonal array of subunits in intercellular junctions of the mouse heart and liver. J Cell Biol 33:C7
Salzman SK, Hirofuji E, Llados-Eckman C, MacEwen GD, Beckman AL (1987) Monoaminergic responses to spinal cord trauma. J Neurosurg 66:431–439
Schatzki PF, Newsome A (1975) Neutralized lanthanum solution: a largely noncolloidal ultrastructural tracer. Stain Technol 50:171–178
Schindelmeiser J, Bergmann M, Lehmenkuhler A, Kersting U (1987) Tracer permeability of rat cortical blood vessels during regional hypothermia. Acta Neuropathol (Berl) 73:349–356
Sharma HS, Dey PK (1986) Influence of long-term immobilization stress on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. J Neurol Sci 72:61–76
Sharma HS, Dey PK (1987) Influence of long-term acute heat exposure on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. Brain Res 424:153–162
Sharma HS, Dey PK (1988) EEG changes following increased blood-brain barrier permeability under long-term immobilization stress in young rats. Neurosci Res 5:224–239
Sharma HS, Olsson Y (1990) Edema formation and cellular alterations following spinal cord injury in the rat and their modification with p-chlorophenylalanine. Acta Neuropathol 79:604–610
Sharma HS, Olsson Y, Dey PK (1989) Early accumulation of serotonin in rat spinal cord subjected to traumatic injury. Relation to edema and blood flow changes. Neuroscience (in press)
Sharma HS, Olsson Y, Dey PK (1989) Changes in bloodbrain barrier and cerebral blood flow following elevation of circulating serotonin level in anaesthetized rats. Brain Res (in press)
Stokes BT, Somerson SK (1987) Spinal cord extracellular microenvironment: can the changes resulting from trauma be graded. Neurochem Pathol 7:47–55
Wahl M, Unterberg A, Baethmann A, Schilling L (1988) Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. J Cereb Blood Flow Metab 8:621–634
Westergaard E (1975) Enhanced vesicular transport of exogenous peroxidase across cerebral vessels induced by serotonin. Acta Neuropathol (Berl) 32:27–42
Westergaard E (1977) The blood-brain barrier to horseradish peroxidase under normal and experimental conditions. Acta Neuropathol (Berl) 39:181–188
Westergaard E (1980) Ultrastructural permeability properties of cerebral microvasculature under normal and experimental conditions after application of tracers. Adv Neurol 28:55–74
Zivin JA, Reid JL, Saavedra JM, Kopin IJ (1975) Quantitative localization of biogenic amines in the spinal cord. Brain Res 99:293–301
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Supported by grants from the Swedish Medical Research Council, project 12X-03020, 1987 Års Stiftelse för Strokeforskning, Trygg Hansa, Wallenius Line Söderbergs Stiftelsen and the Multipel Sclerosis Society of Sweden
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Olsson, Y., Sharma, H.S. & Pettersson, C.Å.V. Effects of p-chlorophenylalanine on microvascular permeability changes in spinal cord trauma. Acta Neuropathol 79, 595–603 (1990). https://doi.org/10.1007/BF00294236
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DOI: https://doi.org/10.1007/BF00294236