Increased substance P immunoreactivity and edema formation following reversible ischemic stroke

  • R. J. Turner
  • P. C. Blumbergs
  • N. R. Sims
  • S. C. Helps
  • K. M. Rodgers
  • R. Vink
Part of the Acta Neurochirurgica Supplementum book series (NEUROCHIRURGICA, volume 96)


Previous results from our laboratory have shown that neurogenic inflammation is associated with edema formation after traumatic brain injury (TBI). This neurogenic inflammation was characterized by increased substance P (SP) immunoreactivity and could be attenuated with administration of SP antagonists with a resultant decrease in edema formation. Few studies have examined whether neurogenic inflammation, as identified by increased SP immunoreactivity, occurs after stroke and its potential role in edema formation. The present study examines SP immunoreactivity and edema formation following stroke.

Experimental stroke was induced in halothane anaesthetized male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion. Increased SP immunoreactivity at 24 hours relative to the non-infarcted hemisphere was observed in perivascular, neuronal, and glial tissue, and within the penumbra of the infarcted hemisphere. It was not as apparent in the infarct core. This increased SP immunoreactivity was associated with edema formation. We conclude that neurogenic inflammation, as reflected by increased SP immunoreactivity, occurs following experimental stroke, and that this may be associated with edema formation. As such, inhibition of neurogenic inflammation may represent a novel therapeutic target for the treatment of edema following reversible, ischemic stroke.


Ischemia edema neuropeptides inflammation 


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  1. 1.
    Alberts MJ (2003) Update on the treatment and prevention of ischaemic stroke. Curr Med Res Opin 19: 438–441PubMedCrossRefGoogle Scholar
  2. 2.
    Alves RV, Campos MM, Santos AR, Calixto JB (1999) Receptor subtypes involved in tachykinin-mediated edema formation. Peptides 20: 921–927PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson MF, Sims NR (1999) Mitochondrial respiratory function and cell death in focal cerebral ischemia. J Neurochem 73: 1189–1199PubMedCrossRefGoogle Scholar
  4. 4.
    Ayata C, Ropper AH (2002) Ischaemic brain oedema. J Clin Neurosci 9: 113–124PubMedCrossRefGoogle Scholar
  5. 5.
    Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD (1996) Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27: 1616–1622; discussion 1623PubMedGoogle Scholar
  6. 6.
    Black PH (2002) Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 16: 622–653PubMedCrossRefGoogle Scholar
  7. 7.
    Campos MM, Calixto JB (2000) Neurokinin mediation of edema and inflammation. Neuropeptides 34: 314–322PubMedCrossRefGoogle Scholar
  8. 8.
    Gartshore G, Patterson J, Macrae IM (1997) Influence of ischemia and reperfusion on the course of brain tissue swelling and blood-brain barrier permeability in a rodent model of transient focal cerebral ischemia. Exp Neurol 147: 353–360PubMedCrossRefGoogle Scholar
  9. 9.
    Green PG, Luo J, Heller PH, Levine JD (1993) Neurogenic and non-neurogenic mechanisms of plasma extravasation in the rat. Neuroscience 52: 735–743PubMedCrossRefGoogle Scholar
  10. 10.
    Holzer P (1998) Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 30: 5–11PubMedGoogle Scholar
  11. 11.
    Kuroiwa 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: 3–11PubMedCrossRefGoogle Scholar
  12. 12.
    Kuroiwa T, Ting P, Martinez H, Klatzo I (1985) The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol (Berl) 68: 122–129PubMedCrossRefGoogle Scholar
  13. 13.
    Lo EH, Singhal AB, Torchilin VP, Abbott NJ (2001) Drug delivery to damaged brain. Brain Res Brain Res Rev 38: 140–148PubMedCrossRefGoogle Scholar
  14. 14.
    Otsuka M, Yoshioka K (1993) Neurotransmitter functions of mammalian tachykinins. Physiol Rev 73: 229–308PubMedGoogle Scholar
  15. 15.
    Quast MJ, Huang NC, Hillman GR, Kent TA (1993) The evolution of acute stroke recorded by multimodal magnetic resonance imaging. Magn Reson Imaging 11: 465–471PubMedCrossRefGoogle Scholar
  16. 16.
    Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V (2002) The tachykinin peptide family. Pharmacol Rev 54: 285–322PubMedCrossRefGoogle Scholar
  17. 17.
    Stumm R, Culmsee C, Schafer MK, Krieglstein J, Weihe E (2001) Adaptive plasticity in tachykinin and tachykinin receptor expression after focal cerebral ischemia is differentially linked to GABAergic and glutamatergic cerebrocortical circuits and cerebrovenular endothelium. J Neurosci 21: 798–811PubMedGoogle Scholar
  18. 18.
    Vink R, Young A, Bennett CJ, Hu X, Connor CO, Cernak I, Nimmo AJ (2003) Neuropeptide release influences brain edema formation after diffuse traumatic brain injury. Acta Neurochir [Suppl] 86: 257–260Google Scholar
  19. 19.
    Warlow CP (1998) Epidemiology of stroke. Lancet 352[Suppl] 3: SIII1–4PubMedGoogle Scholar
  20. 20.
    Williams LS, Weinberger M, Harris LE, Biller J (1999) Measuring quality of life in a way that is meaningful to stroke patients. Neurology 53: 1839–1843PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • R. J. Turner
    • 1
  • P. C. Blumbergs
    • 1
    • 2
  • N. R. Sims
    • 3
  • S. C. Helps
    • 3
  • K. M. Rodgers
    • 1
  • R. Vink
    • 1
  1. 1.Department of PathologyUniversity of AdelaideAdelaideAustralia
  2. 2.Centre for Neurological DiseasesHanson InstituteAdelaideAustralia
  3. 3.Department of Medical Biochemistry and Centre for Neuroscience, School of MedicineFlinders UniversityAdelaideAustralia

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