Skip to main content
Log in

Effects of p-chlorophenylalanine on microvascular permeability changes in spinal cord trauma

An experimental study in the rat using 131I-sodium and lanthanum tracers

  • Regular Papers
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alexander GL, Kopeloff LM, Alexander RB (1988) Low serotonin turnover in cerebral hemispheres of rats primed with p-chlorophenylalanine. Biogen Amin 5:17–24

    Google Scholar 

  2. Andén NE (1974) Effect of acute axotomy (spinal cord transection) on the turnover of 5-hydroxytryptamine. Adv Biochem Psychopharmacol 10:35–43

    Google Scholar 

  3. 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

    Google Scholar 

  4. 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

    Google Scholar 

  5. Anderson EG (1983) The serotonin system of the spinal cord. In: Davidoff RA (ed) Handbook of the spinal cord, vol 1, pp 241–174

  6. Balentine JD (1978) Pathology of experimental spinal cord trauma. II: Ultrastructure of axons and myelin. Lab Invest 39:254–266

    Google Scholar 

  7. Balentine JD (1988) Spinal cord trauma: in search of the meaning of granular axoplasm and vesicular myelin. J Neuropathol Exp Neurol 47:77–92

    Google Scholar 

  8. 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

    Google Scholar 

  9. Barchas J, Usdin E (1977) Serotonin and behaviour. Academic Press, New York, pp 1–177

    Google Scholar 

  10. Beggs JL, Waggener JD (1976) Transendothelial vesicular transport of protein following compression injury to the spinal cord. Lab Invest 34:428–439

    Google Scholar 

  11. 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

    Google Scholar 

  12. Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677

    Google Scholar 

  13. Bundgaard M (1982) Ultrastructure of frog cerebral and pial microvessels and their impermeability to lanthanum ions. Brain Res 241:57–65

    Google Scholar 

  14. 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

    Google Scholar 

  15. 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

    Google Scholar 

  16. Costa E, Gessa GL, Sandler M (1974) Serotonin: new vistas. Histochemistry and pharmacology. Adv Biochem Psychopharmacol 10:22–43

    Google Scholar 

  17. de La Torre JC (1981) Spinal cord injury. Review of basic and applied research. Spine 6:315–335

    Google Scholar 

  18. 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

    Google Scholar 

  19. 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

    Google Scholar 

  20. Dey PK, Sharma HS (1983) Ambient temperature and development of brain edema in anesthetized animals. Indian J Med Res 77:554–563

    Google Scholar 

  21. 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

    Google Scholar 

  22. 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

    Google Scholar 

  23. Doggenweiler CF, Frenk S (1965) Staining properties of lanthanum on cell membranes. Proc Natl Acad Sci USA 53:425–430

    Google Scholar 

  24. Edvinsson L, MacKenzie ET (1977) Amine mechanisms in the cerebral circulation. Pharmacol Rev 28:275–348

    Google Scholar 

  25. Elliott KAC, Jasper H (1949) Measurement of experimentally induced brain swelling and shrinkage. Am J Physiol 157:122–129

    Google Scholar 

  26. Essman W (1978) Serotonin in health and disease. The Central Nervous System, vol 3. Spectrum Publications, New York, pp 1–420

    Google Scholar 

  27. Faden AI (1987) Pharmacotherapy in spinal cord injury: a critical review of recent developments. Clin Neuropharmacol 10:193–204

    Google Scholar 

  28. 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

    Google Scholar 

  29. 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

    Google Scholar 

  30. 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

    Google Scholar 

  31. Hall SM, Williams PL (1971) The distribution of electrondense tracers in peripheral nerve fibres. J Cell Sci 8:541–555

    Google Scholar 

  32. 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

    Google Scholar 

  33. Hsu CY, Halushka PV, Hogan EL, Cox RD (1986) Increased thromboxane level in experimental spinal cord injury. J Neurol Sci 74:289–296

    Google Scholar 

  34. 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

    Google Scholar 

  35. Haydon PG, McCobb DP, Kater SB (1984) Serotonin selectively inhibits growth cone motility and synaptogenesis of specific identified neurones. Science 226:561–564

    Google Scholar 

  36. Jellinger K (1972) Traumatic vascular disease of the spinal cord. Handb Clin Neurol 12:556–630

    Google Scholar 

  37. Johansson B (1981) Indomethacin and cerebrovascular permeability to albumin in acute hypertension and cerebral embolism in the rat. Exp Brain Res 42:331–336

    Google Scholar 

  38. Joo F (1987) A unifying concept on the pathogenesis of brain oedemas. Neuropathol Appl Neurobiol 13:161–176

    Google Scholar 

  39. Julius D, MacDermott AB, Axel R, Jessel TM (1988) Molecular characterization of functional cDNA encoding the serotonin 1c receptor. Science 241:558–564

    Google Scholar 

  40. Koe BK, Weissman A (1966) p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516

    Google Scholar 

  41. 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

    Google Scholar 

  42. 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

    Google Scholar 

  43. MacKenzie ML, Ghabriel MN, Allt G (1987) The bloodnerve barrier: an in vivo lanthanum tracer study. J Anat 154:27–37

    Google Scholar 

  44. 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

    Google Scholar 

  45. 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

    Google Scholar 

  46. Nag S, Robertson DM, Dinsdale HB (1982) Intracerebral arteriolar permeability to lanthanum. Am J Pathol 107: 336–341

    Google Scholar 

  47. 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

    Google Scholar 

  48. 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

    Google Scholar 

  49. 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

    Google Scholar 

  50. Pappius HM, Dadoun R (1987) Effects of injury on the indoleamines in cerebral cortex. J Neurochem 49:321–325

    Google Scholar 

  51. 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

    Google Scholar 

  52. Rapoport SI (1976) Blood-brain-barrier in physiology and medicine. Raven Press, New York, pp 1–327

    Google Scholar 

  53. Revel JP, Hamilton DW (1969) The double nature of the intermediate dense line in peripheral nerve myelin. Anat Rec 163:7–16

    Google Scholar 

  54. Revel JP, Karnovsky MJ (1967) Hexagonal array of subunits in intercellular junctions of the mouse heart and liver. J Cell Biol 33:C7

    Google Scholar 

  55. Salzman SK, Hirofuji E, Llados-Eckman C, MacEwen GD, Beckman AL (1987) Monoaminergic responses to spinal cord trauma. J Neurosurg 66:431–439

    Google Scholar 

  56. Schatzki PF, Newsome A (1975) Neutralized lanthanum solution: a largely noncolloidal ultrastructural tracer. Stain Technol 50:171–178

    Google Scholar 

  57. 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

    Google Scholar 

  58. 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

    Google Scholar 

  59. 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

    Google Scholar 

  60. 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

    Google Scholar 

  61. 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

    Google Scholar 

  62. 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)

  63. 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)

  64. Stokes BT, Somerson SK (1987) Spinal cord extracellular microenvironment: can the changes resulting from trauma be graded. Neurochem Pathol 7:47–55

    Google Scholar 

  65. 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

    Google Scholar 

  66. Westergaard E (1975) Enhanced vesicular transport of exogenous peroxidase across cerebral vessels induced by serotonin. Acta Neuropathol (Berl) 32:27–42

    Google Scholar 

  67. Westergaard E (1977) The blood-brain barrier to horseradish peroxidase under normal and experimental conditions. Acta Neuropathol (Berl) 39:181–188

    Google Scholar 

  68. Westergaard E (1980) Ultrastructural permeability properties of cerebral microvasculature under normal and experimental conditions after application of tracers. Adv Neurol 28:55–74

    Google Scholar 

  69. Zivin JA, Reid JL, Saavedra JM, Kopin IJ (1975) Quantitative localization of biogenic amines in the spinal cord. Brain Res 99:293–301

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00294236

Key words

Navigation