Acta Neuropathologica

, Volume 76, Issue 4, pp 380–387 | Cite as

Foreign and endogenous serum protein extravasation during harmaline tremors or kainic acid seizures in the rat: a comparison

  • R. E. Ruth
  • G. S. Feinerman
Regular Papers


Cerebrovascular permeability to protein (CVP-p) was assessed in rats following the systemic injection of either kainic acid (KA) or harmaline. The extravasation of a foreign (horseradish peroxidase, HRP) or an endogenous (rat immunoglobulin G, IgG) tracer protein was determined using immunohistochemical methods.

During KA-induced seizures, an extravasation of both HRP and presumed IgG occurred in similar forebrain loci; a lamina-specific extravasation occurred within the dorsal hippocampus. During harmaline-induced tremors protein extravasation also occurred, but was tracer dependent. HRP reaction product was observed within the inferior olive, the cortex of the cerebellar vermis and the neocortex. However, IgG-like immunoreactivity was only detected within the circumventricular organs of harmaline-treated rats. Because KA, but not harmaline, is neurotoxic, the results are consistent with an influence of endogenous serum protein extravasation on seizure-related hippocampal damage. Possible homeostatic properties of altered CVP-p are also considered.

Key words

Blood-brain barrier Kainic acid Harmaline Immunoglobulin G 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Balaban CD, Wurpel JND, Severs WG (1984) A specific harmaline-evoked increase in cerebellar 5′-nucleotidase activity. Neurosci Lett 50:111–116Google Scholar
  2. 2.
    Bardin JM, Batini C, Billard JM, Buisseret-Delmas C, Conrath-Verrier M, Corvaja N (1983) Cerebellar output regulation by the climbing and mossy fibers with and without the inferior olive. J Comp Neurol 213:464–477Google Scholar
  3. 3.
    Batini C, Buisseret-Delmas C, Conrath-Verrier M (1981) Harmaline-induced tremor. I. Regional metabolic activity as revealed by 14C-2-deoxyglucose in cat. Exp Brain Res 42:371–382Google Scholar
  4. 4.
    Ben-Ari Y (1985) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403Google Scholar
  5. 5.
    Ben-Ari Y, Tremblay E, Ottersen OP, Naquet R (1979) Evidence suggesting secondary epileptogenic lesions after kainic acid: pre-treatment with diazepam reduces distant but not local damage. Brain Res 165:632–635Google Scholar
  6. 6.
    Ben-Ari Y, Tremblay E, Riche D, Ghilini G, Naquet R (1981) Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 6:1361–1391Google Scholar
  7. 7.
    Berger M, Ben-Ari Y (1983) Autoradiographic visualization of [3H]kainic acid receptor subtypes in the rat hippocampus. Neurosci Lett 39:237–242Google Scholar
  8. 8.
    Bernard JF, Horcholle-Bossavit G (1983) Harmaline-induced rhythm in the lateral reticular nucleus. Arch Ital Biol 121:139–150Google Scholar
  9. 9.
    Bernard JF, Buisseret-Delmas C, Compoint C, Laplante S (1984) Harmaline induced tremor. III. A combined simple units, horseradish peroxidase, and 2-deoxyglucose study of the olivocerebellar system in the rat. Exp Brain Res 57:128–137Google Scholar
  10. 10.
    Black KL, Hoff JT (1985) Leukotrienes increase blood-brain permeability following intraparenchymal injections in rats. Ann Neurol 18:349–351Google Scholar
  11. 11.
    Bishop GA, Ho RH (1984) Substance P and serotonin immunoreactivity in the rat inferior olive. Brain Res Bull 12:105–113Google Scholar
  12. 12.
    Burkhard WP, Bonetti EP, Haefely W (1985) The benzodiazepine antagonist Ro 15-1788 reverses the effect of methyl-B-carboline-3-carboxylate but not of harmaline on cerebellar cGMP and motor performance in mice. Eur J Pharmacol 109:241–247Google Scholar
  13. 13.
    Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J (1983) Induction of brain edema following intracerebral injection of arachidonic acid. Ann Neurol 13: 625–632Google Scholar
  14. 14.
    Collins RC, McLean M, Olney J (1980) Cerebral metabolic response to systemic kainic acid:14C-deoxyglucose studies. Life Sci 27:855–862Google Scholar
  15. 15.
    Collins RC, Lothman E, Olney JW (1983) Status epilepticus in the limbic system: biochemical and pathological changes. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ (eds) Status epilepticus: mechanisms of brain damage and treatment. Raven Press, New York, pp 277–280Google Scholar
  16. 16.
    Conradi NG (1981) Endogenous peroxidase activity in the cerebral and cerebellar cortex of normal adult rats. Acta Neuropathol (Berl) [Suppl]7:3–6Google Scholar
  17. 17.
    Costa E, Guidotti A (1985) Endogenous ligands for benzodiazepine recognition sites. Biochem Pharmacol 34:3399–3403Google Scholar
  18. 18.
    Cotran RS, Karnovsky MJ, Goth A (1968) Resistance of Wistar/Furth rats to the mast cell damaging effect of horseradish peroxidase. J Histochem Cytochem 16:382–383Google Scholar
  19. 19.
    Cserr HF (1975) Bulk flow of cerebral extracellular fluid as a possible mechanism of cerebrospinal fluid-brain exchange. In: Cserr HF (ed) Fluid environment of the brain. Academic Press, New York, pp 215–224Google Scholar
  20. 20.
    de Montigny C, Lamarre Y (1973) Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat. Brain Res 53:81–95Google Scholar
  21. 21.
    Fink RP, Heimer L (1967) Two methods for selective silver impregnation of degenerating axons and their synaptic endings in the central nervous system. Brain Res 4:369–374Google Scholar
  22. 22.
    Fuller TA, Olney JW (1981) Only certain anticonvulsants protect against kainate neurotoxicity. Neurobehav Toxicol Teratol 3:355–361Google Scholar
  23. 23.
    Ginsberg MD, Busto R, Harik SI (1985) Regional blood-brain barrier permeability to water and cerebral blood flow during status epilepticus: insensitivity to norepinephrine depletion. Brain Res 337:59–71Google Scholar
  24. 24.
    Gulati A, Dhawan KN, Shukla R, Srimal RC, Dhawan BN (1985) Evidence for the involvement of histamine in the regulation of blood-brain barrier permeability. Pharmacol Res Commun 17:395–404Google Scholar
  25. 25.
    Hsu S-M, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580Google Scholar
  26. 26.
    Ikuta F, Yoshida Y, Ohama E, Oyanagi K, Takeda S, Yamazaki K, Watabe K (1983) Revised pathophysiology on BBB damage: the edema as an ingeniously provided condition for cell motility and lesion repair. Acta Neuropathol (Berl) [Suppl] 8:103–110Google Scholar
  27. 27.
    Johansson B, Nilsson B (1977) The pathophysiology of the blood-brain barrier dysfunction induced by severe hypercapnia and by epileptic brain activity. Acta Neuropathol (Berl) 38:153–159Google Scholar
  28. 28.
    Karnovsky MJ, Cotran RS (1966) The intercellular passage of exogenous peroxidase across endothelium and mesothelium. Anat Rec 154:365Google Scholar
  29. 29.
    Karoiwa T, Cahn R, Juhler M, Goping G, Campbell G, Klatzo I (1985) Role of extracellular proteins in the dynamics of vasogenic brain edema. Acta Neuropathol (Berl) 66:3–11Google Scholar
  30. 30.
    Klatzo I (1967) Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 24:1–13Google Scholar
  31. 31.
    Lassman H, Petsche U, Kitz K, Baran H, Sperk G, Seitelberger F, Hornykiewicz O (1984) The role of brain edema in epileptic brain damage induced by systemic kainic acid injection. Neuroscience 3:691–704Google Scholar
  32. 32.
    Lee JC, Olszewski J (1961) Increased cerebrovascular permeability of repeated shocks. Neurology 11:515–519Google Scholar
  33. 33.
    Lefauconnier JM, Tayarani Y, Bernard G (1986) Blood-brain permeability to excitatory amino acids. In: Ben-Ari Y, Schwarcz R (eds) Excitatory amino acids and epilepsy. Plenum Press, New York, pp 191–198Google Scholar
  34. 34.
    Llinas R, Volkind RA (1973) The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res 18:69–87Google Scholar
  35. 35.
    London ED, Coyle JT (1979) Specific binding of [3H]kainic acid to receptor sites in rat brain. Mol Pharmacol 15:492–505Google Scholar
  36. 36.
    Longo VG, Massotti M (1985) Effect of tremorigenic agents on the cerebellum: a review of biochemical and electrophysiological data. Int Rev Neurobiol 26:315–329Google Scholar
  37. 37.
    Lothman EW, Collins RC (1981) Kainic acid-induced limbic seizures: metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res 218:229–318Google Scholar
  38. 38.
    Mesulam M-M (1976) The blue reaction product in horseradish peroxidase neurochemistry: incubation and visibility. J Histochem Cytochem 24:1273–1280Google Scholar
  39. 39.
    Mihaly A, Bozoky B (1984) Immunohistochemical localization of extravasated serum albumin in the hippocampus of human subjects with partial and generalized epilepsies and epileptiform convulsions. Acta Neuropathol (Berl) 65:25–34Google Scholar
  40. 40.
    Monaghan DT, Cotman CW (1982) The distribution of [3H]kainic acid-binding sites in rat CNS as determined by autoradiography. Brain Res 252:91–100Google Scholar
  41. 41.
    Nadler JV (1981) Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 29:2031–2042Google Scholar
  42. 42.
    Nitsch C, Klatzo I (1983) Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents. J Neurol Sci 59:305–322Google Scholar
  43. 43.
    Olney JW, Rhee V, Ho O (1974) Kainic acid: a powerful neurotoxic analog of glutamate. Brain Res 77:507–512Google Scholar
  44. 44.
    Pickel VM (1981) Immunocytochemical methods. In: Heimer L, RoBards MJ (eds) Neuroanatomical tract-tracing methods. Plenum Press, New York, pp 483–509Google Scholar
  45. 45.
    Rapaport SI (1976) Blood-brain barrier in physiology and medicine. Raven Press, New York, pp 43–86Google Scholar
  46. 46.
    Rapaport SI, Thompson HK (1975) Osmotic opening of the blood-brain barrier in the monkey without associated neurological deficits. Science 180:971Google Scholar
  47. 47.
    Reese TJ, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217Google Scholar
  48. 48.
    Rodriguez de Turco EB, Morelli de Liberti S, Bazan NG (1983) Stimulation of free fatty acid and diacylglycerol accumulation in cerebrum and cerebellum during bicuculline-induced status epilepticus. Effect of pretreatment withO-methyl-P-tyrosoine andP-chlorophenylalanine. J Neurochem 40:252–259Google Scholar
  49. 49.
    Ruth RE (1982) Kainic-acid lesions of hippocampus produced iontophoretically: the problem of distant damage. Exp Neurol 76:508–527Google Scholar
  50. 50.
    Ruth RE (1984) Increased cerebrovascular permeability to protein during systemic kainic acid seizures. Epilepsia 25:259–268Google Scholar
  51. 51.
    Ruth RE (1986) Extravasated protein as a cause of limbic seizure-induced brain damage: an evaluation using kainic acid. In: Ben-Ari Y, Schwarcz R (eds) Excitatory amino acids and epilepsy. Plenum Press, New York, pp 211–221Google Scholar
  52. 52.
    Savio T, Tempia F (1985) On the Purkinje cell activity increase induced by suppression of inferior olive activity. Exp Brain Res 57:456–463Google Scholar
  53. 53.
    Schwob JE, Fuller T, Price JL, Olney JW (1980) Widespread patterns of neuronal damage following systemic or intracerebral injections of kainic acid: a histological study. Neuroscience 5:991–1014Google Scholar
  54. 54.
    Siesjö BK, Ingvar M, Folbergrova J, Chapman A (1983) Local cerebral circulation and metabolism in bicuculline-induced status epilepticus: relevance for development of cell damage. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ (eds) Status epilepticus: mechanisms of brain damage and treatment. Raven Press, New York, pp 217–230Google Scholar
  55. 55.
    Strosznajder J, Foudin L, Tang W, Sun GY (1983) Serum albumin washing specifically enhances arachidonate incorporation into synaptosomal phosphatidylinositols. J Neurochem 40:84–90Google Scholar
  56. 56.
    Sztriha L, Joo F, Szerdahelyi P, Lelkes Z, Adam G (1985) Kainic acid neurotoxicity: characterization of blood-brain barrier damage. Neurosci Lett 55:233–237Google Scholar
  57. 57.
    Wakai S, Aritake K, Asano T, Takakura K (1982) Selective destruction of the outer leaflet of the capillary endothelial membrane after intracerebral arachidonic acid in the rat. Acta Neuropathol (Berl) 58:303–306Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • R. E. Ruth
    • 1
    • 2
  • G. S. Feinerman
    • 1
    • 2
  1. 1.Neuroteratology LaboratoryInstitute for the Study of Developmental DisabilitiesChicagoUSA
  2. 2.Committee on NeuroscienceUniversity of Illinois at ChicagoChicagoUSA

Personalised recommendations