Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition associated with the development of early brain injury (EBI) and delayed cerebral ischemia (DCI). Pharmacological treatment of vasospasm following aSAH currently mainly comprises nimodipine administration. In the past few years, many drugs that can potentially benefit cases of subarachnoid hemorrhage have become available. The objective of this review is to critically assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) following aSAH. A systematic literature review was conducted following PRISMA guidelines. The search was aimed at studies addressing aSAH and NSAIDs during the 2010 to 2019 period, and it yielded 13 articles. Following the application of search criteria, they were divided into two groups, one containing 6 clinical articles and the other containing 7 experimental articles on animal models of aSAH. Inflammatory cerebral changes after aneurysm rupture contribute to the development of EBI, DCI and cerebral vasospasm. It appears that NSAIDs (especially coxibs) are even more effective in reducing vasospasm than nimodipine. Other beneficial effects of NSAIDs include reduction in mortality, improved functional outcome and increased hypoaggregability. However, despite these positive effects, there is only one randomized, double-blind, placebo-controlled trial showing a tendency towards a better outcome with lower incidence of vasospasm or mortality in patients following aSAH.

Cellular and Molecular Neurobiology Research Group Department of Anatomy Faculty of Medicine Masaryk University Brno Czech Republic

Department of Neurosurgery St Anne's University Hospital Brno Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Department of Neurosurgery St Anne's University Hospital Brno Pekarska 53 656 91 Brno Czech Republic

Zobrazit více v PubMed

Ansar S, Larsen C, Maddahi A, Edvinsson L (2010) Subarachnoid hemorrhage induces enhanced expression of thromboxane A2 receptors in rat cerebral arteries. Brain Res 1316:163–172. https://doi.org/10.1016/j.brainres.2009.12.031 PubMed DOI

Brueggemann LI, Mani BK, Mackie AR, Cribbs LL, Byron KL (2010) Novel actions of nonsteroidal anti-inflammatory drugs on vascular ion channels: accounting for cardiovascular side effects and identifying new therapeutic applications. Mol Cell Pharmacol 2:15–19 PubMed PMC

Brune K, Patrignani P (2015) New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res 8:105–118. https://doi.org/10.2147/JPR.S75160 PubMed DOI PMC

Çelik Ö, Bilginer B, Korkmaz A, Gürgör PN, Bavbek M, Özgen T, Ziyal İ (2011) Effects of intramuscular parecoxib administration on vasospasm in an experimental subarachnoid hemorrhage model. Int J Neurosci 121:316–322. https://doi.org/10.3109/00207454.2011.556284 PubMed DOI

Chang C-Z, Wu S-C, Lin C-L, Kwan A-L (2015) Parecoxib, a selective cyclooxygenase inhibitor, attenuates C-Jun N-terminal kinase activation in experimental subarachnoid hemorrhage induced early brain injury. J Neurol Neurophysiol 6. https://doi.org/10.4172/2155-9562.1000294

Choi HA, Ko S-B, Chen H, Gilmore E, Carpenter AM, Lee D, Claassen J, Mayer SA, Schmidt JM, Lee K, Connelly ES, Paik M, Badjatia N (2012) Acute effects of nimodipine on cerebral vasculature and brain metabolism in high grade subarachnoid hemorrhage patients. Neurocrit Care 16:363–367. https://doi.org/10.1007/s12028-012-9670-8 PubMed DOI

Etminan N, Chang H-S, Hackenberg K, de Rooij NK, Vergouwen MDI, Rinkel GJE, Algra A (2019) Worldwide incidence of aneurysmal subarachnoid hemorrhage according to region, time period, blood pressure, and smoking prevalence in the population: a systematic review and meta-analysis. JAMA Neurol 76:588–597. https://doi.org/10.1001/jamaneurol.2019.0006 PubMed DOI PMC

Fisher CL, Demel SL (2019) Nonsteroidal anti-inflammatory drugs: a potential pharmacological treatment for intracranial aneurysm. Cerebrovasc Dis Extra 9:31–45. https://doi.org/10.1159/000499077 PubMed DOI PMC

Frontera JA, Provencio JJ, Sehba FA, McIntyre TM, Nowacki AS, Gordon E, Weimer JM, Aledort L (2017) The role of platelet activation and inflammation in early brain injury following subarachnoid hemorrhage. Neurocrit Care 26:48–57. https://doi.org/10.1007/s12028-016-0292-4 PubMed DOI PMC

Ghodsi SM, Mohebbi N, Naderi S, Anbarloie M, Aoude A, Habibi Pasdar SS (2015) Comparative efficacy of meloxicam and placebo in vasospasm of patients with subarachnoid hemorrhage. Iran J Pharm Res IJPR 14:125–130 PubMed

Hinz B, Cheremina O, Brune K (2007) Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J. https://doi.org/10.1096/fj.07-8506com

Jack H, Zhang JH (2013) Does prevention of vasospasm in subarachnoid hemorrhage improve clinical outcome? No. Stroke 44:S34–S36. https://doi.org/10.1161/STROKEAHA.111.000686 DOI

Huang H, Al-Shabrawey M, Wang M-H (2016) Cyclooxygenase- and cytochrome P450-derived eicosanoids in stroke. Prostaglandins Other Lipid Mediat 122:45–53. https://doi.org/10.1016/j.prostaglandins.2015.12.007 PubMed DOI

Imai T, Iwata S, Hirayama T, Nagasawa H, Nakamura S, Shimazawa M, Hara H (2019) Intracellular Fe 2+ accumulation in endothelial cells and pericytes induces blood-brain barrier dysfunction in secondary brain injury after brain hemorrhage. Sci Rep 9:1–16. https://doi.org/10.1038/s41598-019-42370-z DOI

Schiefecker AJ, Rass V, Gaasch M, Kofler M, Thomé C, Humpel C, Ianosi B, Hackl WO, Beer R, Pfausler B, Schmutzhard E, Helbok R (2019) Brain extracellular interleukin-6 levels decrease following antipyretic therapy with diclofenac in patients with spontaneous subarachnoid hemorrhage. Ther Hypothermia Temp Manag 9(1):48–55. https://doi.org/10.1089/ther.2018.0001 PubMed DOI

Jasiecka A, Maślanka T, Jaroszewski JJ (2014) Pharmacological characteristics of metamizole. Pol J Vet Sci 17:207–214 DOI

Jedrzejowska-Szypulka H, Larysz-Brysz M, Kukla M, Snietura M, Lewin-Kowalik J (2009) Neutralization of interleukin-1β reduces vasospasm and alters cerebral blood vessel density following experimental subarachnoid hemorrhage in rats. https://www.ingentaconnect.com/content/ben/cnr/2009/00000006/00000002/art00003 .

Ji X, Nishihashi T, Trandafir CC, Wang A, Shimizu Y, Kurahashi K (2007) Pharmacological nature of nicotine-induced contraction in the rat basilar artery: involvement of arachidonic acid metabolites. Eur J Pharmacol 577:109–114. https://doi.org/10.1016/j.ejphar.2007.08.011 PubMed DOI

Ji X, Wang A, Trandafir CC, Kurahashi K (2013) Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to arachidonic acid metabolites signaling pathway. J Stroke Cerebrovasc Dis 22:951–958. https://doi.org/10.1016/j.jstrokecerebrovasdis.2011.12.001 PubMed DOI

Kim GH, Kellner CP, Hahn DK, Desantis BM, Musabbir M, Starke RM, Rynkowski M, Komotar RJ, Otten ML, Sciacca R, Schmidt JM, Mayer SA, Connolly ES (2008) Monocyte chemoattractant protein–1 predicts outcome and vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 109:38–43. https://doi.org/10.3171/JNS/2008/109/7/0038 PubMed DOI

Laher I, Zhang JH (2001) Protein kinase C and cerebral vasospasm. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 21:887–906. https://doi.org/10.1097/00004647-200108000-00001 DOI

Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ (2011) Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 31:17–35. https://doi.org/10.1038/jcbfm.2010.191 PubMed DOI

Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS (2000) Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 40:124–132. https://doi.org/10.1177/00912700022008766 PubMed DOI

Li Y, Luo D, Chen X, Li J, Yan L, Li T, Zhao Y, Liu H, Ji X, Ma X (2017) Involvement of arachidonic acid metabolites pathway and nicotinic acetylcholine receptors (nAChRs) on nicotine-induced contractions (or relaxations) in the basilar artery. Int J Pharmacol 13:1–10. https://doi.org/10.3923/ijp.2017.1.10 DOI

Young AM, Karri SK, Ogilvy CS (2012) Non-steroidal anti-inflammatory drugs used as a treatment modality in subarachnoid hemorrhage. https://www.ingentaconnect.com/content/ben/cds/2012/00000007/00000003/art00003 .

Mani BK, Brueggemann LI, Cribbs LL, Byron KL (2011) Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery. Br J Pharmacol 164:237–249. https://doi.org/10.1111/j.1476-5381.2011.01273.x PubMed DOI PMC

Mani BK, O’Dowd J, Kumar L, Brueggemann LI, Ross M, Byron KL (2013) Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm. J Cardiovasc Pharmacol 61:51–62. https://doi.org/10.1097/FJC.0b013e3182771708 PubMed DOI PMC

Mee E, Dorrance D, Lowe D, Neil-Dwyer G (1988) Controlled study of nimodipine in aneurysm patients treated early after subarachnoid hemorrhage. Neurosurgery 22:484–491. https://doi.org/10.1227/00006123-198803000-00006 PubMed DOI

Miller BA, Turan N, Chau M, Pradilla G (2014) Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed Res Int 2014:1–16. https://doi.org/10.1155/2014/384342 DOI

Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097 PubMed DOI PMC

Munakata A, Naraoka M, Katagai T, Shimamura N, Ohkuma H (2016) Role of cyclooxygenase-2 in relation to nitric oxide and endothelin-1 on pathogenesis of cerebral vasospasm after subarachnoid hemorrhage in rabbit. Transl Stroke Res 7:220–227. https://doi.org/10.1007/s12975-016-0466-6 PubMed DOI

Muroi C, Hugelshofer M, Seule M, Keller E (2014) The impact of nonsteroidal anti-inflammatory drugs on inflammatory response after aneurysmal subarachnoid hemorrhage. Neurocrit Care 20:240–246. https://doi.org/10.1007/s12028-013-9930-2 PubMed DOI

Nassiri F, Ibrahim GM, Badhiwala JH, Witiw CD, Mansouri A, Alotaibi NM, Macdonald RL (2016) A propensity score-matched study of the use of non-steroidal anti-inflammatory agents following aneurysmal subarachnoid hemorrhage. Neurocrit Care 25:351–358. https://doi.org/10.1007/s12028-016-0266-6 PubMed DOI

de Oliveira Manoel AL, Macdonald RL (2018) Neuroinflammation as a target for intervention in subarachnoid hemorrhage. Front Neurol 9. https://doi.org/10.3389/fneur.2018.00292

Olsen MH, Orre M, Leisner ACW, Rasmussen R, Bache S, Welling K-L, Eskesen V, Møller K Delayed cerebral ischaemia in patients with aneurysmal subarachnoid haemorrhage: functional outcome and long-term mortality. Acta Anaesthesiol Scand 63(9):1191–1199. https://doi.org/10.1111/aas.13412

Parkhutik V, Lago A, Tembl JI, Rubio C, Fuset MP, Vallés J, Santos MT, Moscardo A (2012) Influence of COX-inhibiting analgesics on the platelet function of patients with subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 21:755–759. https://doi.org/10.1016/j.jstrokecerebrovasdis.2011.04.002 PubMed DOI

Peeyush Kumar T, McBride DW, Dash PK, Matsumura K, Rubi A, Blackburn SL (2019) Endothelial cell dysfunction and injury in subarachnoid hemorrhage. Mol Neurobiol 56:1992–2006. https://doi.org/10.1007/s12035-018-1213-7 PubMed DOI

Petruk KC, West M, Mohr G, Weir BKA, Benoit BG, Gentili F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron GS, Tucker WS, Purves GB, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB, Godon A (1988) Nimodipine treatment in poor-grade aneurysm patients: results of a multicenter double-blind placebo-controlled trial. J Neurosurg 68:505–517. https://doi.org/10.3171/jns.1988.68.4.0505 PubMed DOI

Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P (1989) Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 298:636–642 DOI

Pluta RM (2008) Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl 104:139–147 DOI

Pluta RM, Afshar JK, Boock RJ, Oldfield EH (1998) Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage. J Neurosurg 88:557–561. https://doi.org/10.3171/jns.1998.88.3.0557 PubMed DOI

Porchet F, Chioléro R, de Tribolet N (1995) Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid haemorrhage. Acta Neurochir 137:62–69. https://doi.org/10.1007/BF02188783 PubMed DOI

Prunell GF, Mathiesen T, Diemer NH, Svendgaard N-A (2003) Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery 52:165–175; discussion 175-176. https://doi.org/10.1097/00006123-200301000-00022 PubMed DOI

Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P (2012) Novel bioactive metabolites of dipyrone (metamizol). Bioorg Med Chem 20:101–107. https://doi.org/10.1016/j.bmc.2011.11.028 PubMed DOI

Sabri M, Lass E, Macdonald RL (2013) Early brain injury: a common mechanism in subarachnoid hemorrhage and global cerebral ischemia. Stroke Res. Treat, In https://www.hindawi.com/journals/srt/2013/394036/ .

Schiefecker AJ, Pfausler B, Beer R, Sohm F, Sabo J, Knauseder V, Fischer M, Dietmann A, Hackl WO, Thomé C, Schmutzhard E, Helbok R (2013) Parenteral diclofenac infusion significantly decreases brain-tissue oxygen tension in patients with poor-grade aneurysmal subarachnoid hemorrhage. Crit Care 17:R88. https://doi.org/10.1186/cc12714 PubMed DOI PMC

Schiefecker AJ, Rass V, Gaasch M, Kofler M, Thomé C, Humpel C, Ianosi B, Hackl WO, Beer R, Pfausler B, Schmutzhard E, Helbok R (2018) Brain extracellular interleukin-6 levels decrease following antipyretic therapy with diclofenac in patients with spontaneous subarachnoid hemorrhage. Ther Hypothermia Temp Manag 9:48–55. https://doi.org/10.1089/ther.2018.0001 PubMed DOI

Sehba FA, Bederson JB (2006) Mechanisms of acute brain injury after subarachnoid hemorrhage. Neurol Res 28:381–398 DOI

Silav G, Ergün H, Dolgun H, Sancak T, Sargon MF, Egemen N (2017) Dipyrone attenuates cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. J Neurosurg Sci 61:380–387. https://doi.org/10.23736/S0390-5616.16.03068-X PubMed DOI

Stanley C, O’Sullivan SE (2014) Vascular targets for cannabinoids: animal and human studies. Br J Pharmacol 171:1361–1378. https://doi.org/10.1111/bph.12560 PubMed DOI PMC

Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G (2013) European stroke organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis 35:93–112. https://doi.org/10.1159/000346087 PubMed DOI

Thampatty BP, Sherwood PR, Gallek MJ, Crago EA, Ren D, Hricik AJ, Kuo C-WJ, Klamerus MM, Alexander SA, Bender CM, Hoffman LA, Horowitz MB, Kassam AB, Poloyac SM (2011) Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia. Neurocrit Care 15:19–27. https://doi.org/10.1007/s12028-011-9508-9 PubMed DOI PMC

Tran Dinh Y, Jomaa A, Callebert J, Reynier-Rebuffel AM, Tedgui A, Savarit A, Sercombe R (2001) Overexpression of cyclooxygenase-2 in rabbit basilar artery endothelial cells after subarachnoid hemorrhage. Neurosurgery 48:626–633; discussion 633. https://doi.org/10.1097/00006123-200103000-00037 PubMed DOI

Vellimana AK, Milner E, Azad TD, Harries MD, Zhou M-L, Gidday JM, Han BH, Zipfel GJ (2011) Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 42:776–782. https://doi.org/10.1161/STROKEAHA.110.607200 PubMed DOI

Vergouwen Mervyn DI, Don I, Loch MR (2011) Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke 42:924–929. https://doi.org/10.1161/STROKEAHA.110.597914 PubMed DOI

Weir BK, Kongable GL, Kassell NF, Schultz JR, Truskowski LL, Sigrest A (1998) Cigarette smoking as a cause of aneurysmal subarachnoid hemorrhage and risk for vasospasm: a report of the Cooperative Aneurysm Study. J Neurosurg 89:405–411. https://doi.org/10.3171/jns.1998.89.3.0405 PubMed DOI

The blood-brain barrier and the neurovascular unit in subarachnoid hemorrhage: molecular events and potential treatments