Substance P antagonists as a therapeutic approach to improving outcome following traumatic brain injury (original) (raw)

Summary

Although a number of secondary injury factors are known to contribute to the development of morphological injury and functional deficits following traumatic brain injury, accumulating evidence has suggested that neuropeptides. and in particular substance P, may play a critical role. Substance P is released early following acute injury to the CNS as part of a neurogenic inflammatory response. In so doing, it facilitates an increase in the permeability of the blood—brain barrier and the development of vasogenic edema. At the cellular level, substance P has been shown to directly result in neuronal cell death; functionally, substance P has been implicated in learning and memory, mood and anxiety, stress mechanisms, emotion-processing, migraine, emesis, pain, and seizures, all of which may be adversely affected after brain injury. Inhibition of post-traumatic substance P activity, either by preventing release or by antagonism of the neurokinin-1 receptor, has consistently resulted in a profound decrease in development of edema and marked improvements in functional outcome. This review summarizes the current evidence supporting a role for substance P in acute brain injury.

Key Words: Neurotrauma, inflammation, edema, substance P, tachykinins

References

• 1.Tagliaferri F, Compagnone C, Korsic M, Servadei F, Kraus J. A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 2006;148:255–268. doi: 10.1007/s00701-005-0651-y. [DOI] [PubMed] [Google Scholar]
• 2.Blumbergs PC, Reilly PL, Vink R. Trauma. In: Love S, Louis DN, Ellison DW, editors. Greenfield’s neuropathology. 8th ed. London: Hodder Arnold; 2008. pp. 733–832. [Google Scholar]
• 3.McIntosh TK, Smith DH, Meaney DF, Kotapka MJ, Gennarelli TA, Graham DI. Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. Lab Invest. 1996;74:315–342. [PubMed] [Google Scholar]
• 4.Feickert HJ, Drommer S, Heyer R. Severe head injury in children: impact of risk factors on outcome. J Trauma. 1999;47:33–38. doi: 10.1097/00005373-199907000-00008. [DOI] [PubMed] [Google Scholar]
• 5.Marmarou A, Fatouros PP, Barzó P, et al. Contribution of edema and cerebral blood volume to traumatic brain swelling in head-injured patients. J Neurosurg. 2000;93:183–193. doi: 10.3171/jns.2000.93.2.0183. [DOI] [PubMed] [Google Scholar]
• 6.Brain Trauma Foundation. American Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care Initial management. J Neurotrauma. 2000;17:463–469. doi: 10.1089/neu.2000.17.463. [DOI] [PubMed] [Google Scholar]
• 7.Nimmo AJ, Cernak I, Heath DL, Hu X, Bennett CJ, Vink R. Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats. Neuropeptides. 2004;38:40–47. doi: 10.1016/j.npep.2003.12.003. [DOI] [PubMed] [Google Scholar]
• 8.Donkin JJ, Nimmo AJ, Cernak I, Blumbergs PC, Vink R. A critical role for substance P in the development of traumatic brain edema. J Cereb Blood Flow Metab. 2009;29:1388–1398. doi: 10.1038/jcbfm.2009.63. [DOI] [PubMed] [Google Scholar]
• 9.Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V. The tachykinin peptide family. Pharmacol Rev. 2002;54:285–322. doi: 10.1124/pr.54.2.285. [DOI] [PubMed] [Google Scholar]
• 10.von Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol. 1931;72:74–87. doi: 10.1113/jphysiol.1931.sp002763. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 11.Lembeck F. Central transmission of afferent impulses: III. Incidence and significance of the substance P in the dorsal roots of the spinal cord [In German] Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1953;219:197–213. doi: 10.1007/BF00246293. [DOI] [PubMed] [Google Scholar]
• 12.Otsuka M, Yoshioka K. Neurotransmitter functions of mammalian tachykinins. Physiol Rev. 1993;73:229–308. doi: 10.1152/physrev.1993.73.2.229. [DOI] [PubMed] [Google Scholar]
• 13.Kaplanski J, Pruneau D, Asa I, et al. LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces brain edema and improves long-term neurological function recovery after closed head trauma in rats. J Neurotrauma. 2002;19:953–964. doi: 10.1089/089771502320317104. [DOI] [PubMed] [Google Scholar]
• 14.Kaplanski J, Asa I, Artru AA, et al. LF 16-0687 Ms, a new bradykinin B2 receptor antagonist, decreases ex vivo brain tissue prostaglandin E2 synthesis after closed head trauma in rats. Resuscitation. 2003;56:207–213. doi: 10.1016/S0300-9572(02)00371-4. [DOI] [PubMed] [Google Scholar]
• 15.Marmarou A, Nichols J, Burgess J, et al. Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. J Neurotrauma. 1999;16:431–444. doi: 10.1089/neu.1999.16.431. [DOI] [PubMed] [Google Scholar]
• 16.Zweckberger K, Plesnila N. Anatibant, a selective non-peptide bradykinin B2 receptor antagonist, reduces intracranial hypertension and histopathological damage after experimental traumatic brain injury. Neurosci Lett. 2009;454:115–117. doi: 10.1016/j.neulet.2009.02.014. [DOI] [PubMed] [Google Scholar]
• 17.Rodi D, Couture R, Ongali B, Simonato M. Targeting kinin receptors for the treatment of neurological diseases. Curr Pharm Des. 2005;11:1313–1326. doi: 10.2174/1381612053507422. [DOI] [PubMed] [Google Scholar]
• 18.Chiang WC, Chien CT, Lin WW, et al. Early activation of bradykinin B2 receptor aggravates reactive oxygen species generation and renal damage in ischemia/reperfusion injury. Free Radic Biol Med. 2006;41:1304–1314. doi: 10.1016/j.freeradbiomed.2006.07.011. [DOI] [PubMed] [Google Scholar]
• 19.Noda M, Kariura Y, Pannasch U, et al. Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia. J Neurochem. 2007;101:397–410. doi: 10.1111/j.1471-4159.2006.04339.x. [DOI] [PubMed] [Google Scholar]
• 20.Bayliss WM. On the origin from the spinal cord of the vaso-dilator fibres of the hind-limb, and on the nature of these fibres. J Physiol. 1901;26:173–209. doi: 10.1113/jphysiol.1901.sp000831. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 21.Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun. 2002;16:622–653. doi: 10.1016/S0889-1591(02)00021-1. [DOI] [PubMed] [Google Scholar]
• 22.Geppetti P, Bertrand C, Ricciardolo FL, Nadel JA. New aspects on the role of kinins in neurogenic inflammation. Can J Physiol Pharmacol. 1995;73:843–847. doi: 10.1139/y95-115. [DOI] [PubMed] [Google Scholar]
• 23.Ferrari MD. Migraine. Lancet. 1998;351:1043–1051. doi: 10.1016/S0140-6736(97)11370-8. [DOI] [PubMed] [Google Scholar]
• 24.Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev. 1999;51:159–212. [PubMed] [Google Scholar]
• 25.Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824. doi: 10.1038/39807. [DOI] [PubMed] [Google Scholar]
• 26.Szolcsányi J, Mózsik G. Effects of capsaicin on the development of gastric mucosal damage by different necrotizing agents and of gastric cytoprotection by PGI2 atropine and cimetidine on rats. Acta Physiol Hung. 1984;64:287–291. [PubMed] [Google Scholar]
• 27.Marmarou A. A review of progress in understanding the patho-physiology and treatment of brain edema. Neurosurg Focus. 2007;22(5):E1–E1. doi: 10.3171/foc.2007.22.5.2. [DOI] [PubMed] [Google Scholar]
• 28.Nag S, Manias JL, Stewart DJ. Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol. 2009;118:197–217. doi: 10.1007/s00401-009-0541-0. [DOI] [PubMed] [Google Scholar]
• 29.Habgood MD, Bye N, Dziegielewska KM, et al. Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur J Neurosci. 2007;25:231–238. doi: 10.1111/j.1460-9568.2006.05275.x. [DOI] [PubMed] [Google Scholar]
• 30.Marmarou A, Portella G, Barzo P, et al. Distinguishing between cellular and vasogenic edema in head injured patients with focal lesions using magnetic resonance imaging. Acta Neurochir Suppl (Wien) 2000;76:349–351. doi: 10.1007/978-3-7091-6346-7_72. [DOI] [PubMed] [Google Scholar]
• 31.Beaumont A, Marmarou A, Hayasaki K, et al. The permissive nature of blood brain barrier (BBB) opening in edema formation following traumatic brain injury. Acta Neurochir Suppl (Wien) 2000;76:125–129. doi: 10.1007/978-3-7091-6346-7_26. [DOI] [PubMed] [Google Scholar]
• 32.Arvin B, Neville LF, Barone FC, Feuerstein GZ. The role of inflammation and cytokines in brain injury. Neurosci Biobehav Rev. 1996;20:445–452. doi: 10.1016/0149-7634(95)00026-7. [DOI] [PubMed] [Google Scholar]
• 33.Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002;8:101–105. doi: 10.1097/00075198-200204000-00002. [DOI] [PubMed] [Google Scholar]
• 34.Saria A. Substance P in sensory nerve fibres contributes to the development of oedema in the rat hind paw after thermal injury. Br J Pharmacol. 1984;82:217–222. doi: 10.1111/j.1476-5381.1984.tb16461.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 35.Yonehara N, Shibutani T, Inoki R. Contribution of substance P to heat-induced edema in rat paw. J Pharmacol Exp Ther. 1987;242:1071–1076. [PubMed] [Google Scholar]
• 36.De AK, Ghosh JJ. Inflammatory responses induced by substance P in rat paw. Indian J Exp Biol. 1990;28:946–948. [PubMed] [Google Scholar]
• 37.Donkin JJ, Cemak I, Rodgers KM, Vink R. Mild concussive head injury results in increased brain substance P immunoreactivity. In: 7th International Neurotrauma Symposium. Bologna: Medimond International Proceedings, 2004:75-78.
• 38.Zacest AC, Vink R, Manavis J, Sarvestani GT, Blumbergs PC. Substance P immunoreactivity increases following human traumatic brain injury. Acta Neurochir Suppl (Wien) 2009;106:211–216. doi: 10.1007/978-3-211-98811-4_39. [DOI] [PubMed] [Google Scholar]
• 39.Brain SD, Williams TJ. Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br J Pharmacol. 1985;86:855–860. doi: 10.1111/j.1476-5381.1985.tb11107.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 40.Hökfelt T, Pemow B, Wahren J, Substance P. a pioneer amongst neuropeptides. J Intern Med. 2001;249:27–40. doi: 10.1046/j.0954-6820.2000.00773.x. [DOI] [PubMed] [Google Scholar]
• 41.Malcangio M, Ramer MS, Jones MG, McMahon SB. Abnormal substance P release from the spinal cord following injury to primary sensory neurons. Eur J Neurosci. 2000;12:397–399. doi: 10.1046/j.1460-9568.2000.00946.x. [DOI] [PubMed] [Google Scholar]
• 42.Sharma HS, Nyberg F, Olsson Y, Dey PK. Alteration of substance P after trauma to the spinal cord: an experimental study in the rat. Neuroscience. 1990;38:205–212. doi: 10.1016/0306-4522(90)90386-I. [DOI] [PubMed] [Google Scholar]
• 43.Annunziata P, Cioni C, Santonini R, Paccagnini E. Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium. J Neuroimmunol. 2002;131:41–49. doi: 10.1016/S0165-5728(02)00262-X. [DOI] [PubMed] [Google Scholar]
• 44.Stumm R, Culmsee C, Schafer MK, Krieglstein J, Weihe E. 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. 2001;21:798–811. doi: 10.1523/JNEUROSCI.21-03-00798.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 45.Turner RJ, Blumbergs PC, Sims NR, Helps SC, Rodgers KM, Vink R. Increased substance P immunoreactivity and edema formation following reversible ischemic stroke. Acta Neurochir Suppl (Wien) 2006;96:263–266. doi: 10.1007/3-211-30714-1_56. [DOI] [PubMed] [Google Scholar]
• 46.Bruno G, Tega F, Bruno A, et al. The role of substance P in cerebral ischemia. Int J Immunopathol Pharmacol. 2003;16:67–72. doi: 10.1177/039463200301600110. [DOI] [PubMed] [Google Scholar]
• 47.Mantyh PW, Johnson DJ, Boehmer CG, et al. Substance P receptor binding sites are expressed by glia in vivo after neuronal injury. Proc Natl Acad Sci U S A. 1989;86:5193–5197. doi: 10.1073/pnas.86.13.5193. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 48.Lin RC. Reactive astrocytes express substance-P immunoreactivity in the adult forebrain after injury. Neuroreport. 1995;7:310–312. [PubMed] [Google Scholar]
• 49.Castro-Obregón S, Rao RV, del Rio G, et al. Alternative, nonapoptotic programmed cell death: mediation by arrestin-2, ERK2 and Nur77. J Biol Chem. 2004;279:17543–17553. doi: 10.1074/jbc.M312363200. [DOI] [PubMed] [Google Scholar]
• 50.Alvaro G, Di Fabio R. Neurokinin 1 receptor antagonists: current prospects. Curr Opin Drug Discov Devel. 2007;10:613–621. [PubMed] [Google Scholar]
• 51.Liu H, Mazarati AM, Katsumori H, Sankar R, Wasterlain CG. Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus. Proc Natl Acad Sci U S A. 1999;96:5286–5291. doi: 10.1073/pnas.96.9.5286. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 52.Leban J, Rackur G, Yamaguchi I, et al. Synthesis of substance P analogs and agonistic and antagonistic activities. Acta Chem Scand B. 1979;33:664–668. doi: 10.3891/acta.chem.scand.33b-0664. [DOI] [PubMed] [Google Scholar]
• 53.Folkers K, Hörig J, Rosell S, Björkroth U. Chemical design of antagonists of substance P. Acta Physiol Scand. 1981;111:505–506. doi: 10.1111/j.1748-1716.1981.tb06771.x. [DOI] [PubMed] [Google Scholar]
• 54.Engberg G, Svensson TH, Rosell S, Folkers K. A synthetic peptide as an antagonist of substance P. Nature. 1981;293:222–223. doi: 10.1038/293222a0. [DOI] [PubMed] [Google Scholar]
• 55.Snider RM, Longo KP, Drozda SE, Lowe JA, Leeman SE. Effect of CP-96,345, a nonpeptide substance P receptor antagonist, on salivation in rats. Proc Natl Acad Sci U S A. 1991;88:10042–10044. doi: 10.1073/pnas.88.22.10042. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 56.MacLeod AM, Cascieri MA, Merchant KJ, et al. Synthesis and biological evaluation of NK1 antagonists derived from l-tryptophan. J Med Chem. 1995;38:934–941. doi: 10.1021/jm00006a012. [DOI] [PubMed] [Google Scholar]
• 57.Rupniak NM, Kramer MS. Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol Sci. 1999;20:485–490. doi: 10.1016/S0165-6147(99)01396-6. [DOI] [PubMed] [Google Scholar]
• 58.Santarelli L, Gobbi G, Debs PC, et al. Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci U S A. 2001;98:1912–1917. doi: 10.1073/pnas.041596398. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 59.Ranga K, Krishnan R. Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry. 2002;63(Suppl 11):25–29. [PubMed] [Google Scholar]
• 60.Vink R, Donkin JJ, Cruz MI, Nimmo AJ, Cemak I. A substance P antagonist increases brain intracellular free magnesium concentration after diffuse traumatic brain injury in rats. J Am Coll Nutr. 2004;23:538S–540S. doi: 10.1080/07315724.2004.10719398. [DOI] [PubMed] [Google Scholar]
• 61.Vink R. Nuclear magnetic resonance characterization of secondary mechanisms following traumatic brain injury. Mol Chem Neuropathol. 1993;18:279–297. doi: 10.1007/BF03160120. [DOI] [PubMed] [Google Scholar]
• 62.Vink R, O’Connor CA, Nimmo AJ, Heath DL. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Neurosci Lett. 2003;336:41–44. doi: 10.1016/S0304-3940(02)01244-2. [DOI] [PubMed] [Google Scholar]
• 63.Vink R, Nimmo AJ. Multifunctional drugs for head injury. Neurotherapeutics. 2009;6:28–42. doi: 10.1016/j.nurt.2008.10.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 64.Yu Z, Cheng G, Huang X, Li K, Cao X. Neurokinin-1 receptor antagonist SR140333: a novel type of drug to treat cerebral ischemia. Neuroreport. 1997;8:2117–2119. doi: 10.1097/00001756-199707070-00006. [DOI] [PubMed] [Google Scholar]
• 65.Turner R, Vink R. Inhibition of neurogenic inflammation as a novel treatment for ischemic stroke. Drug News Perspect. 2007;20:221–226. doi: 10.1358/dnp.2007.20.4.1103527. [DOI] [PubMed] [Google Scholar]
• 66.Souza DG, Mendonça VA, de A Castro MS, Poole S, Teixeira MM. Role of tachykinin NK receptors on the local and remote injuries following ischaemia and reperfusion of the superior mesenteric artery in the rat. Br J Pharmacol. 2002;135:303–312. doi: 10.1038/sj.bjp.0704464. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 67.Kramer JH, Phillips TM, Weglicki WB. Magnesium deficiency enhanced post-ischemic myocardial injury is reduced by substance P receptor blockade. J Cardiol. 1997;29:97–110. doi: 10.1006/jmcc.1996.0255. [DOI] [PubMed] [Google Scholar]
• 68.Heath DL, Vink R. Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration. Brain Res. 1996;738:150–153. doi: 10.1016/0006-8993(96)00957-2. [DOI] [PubMed] [Google Scholar]
• 69.Campos MM, Calixto JB. Neurokinin mediation of edema and inflammation. Neuropeptides. 2000;34:314–322. doi: 10.1054/npep.2000.0823. [DOI] [PubMed] [Google Scholar]
• 70.Kashiba H, Ueda Y, Senba E. Systemic capsaicin in the adult rat differentially affects gene expression for neuropeptides and neurotrophin receptors in primary sensory neurons. Neuroscience. 1997;76:299–312. doi: 10.1016/S0306-4522(96)00334-X. [DOI] [PubMed] [Google Scholar]