Abstract
Germinal matrix hemorrhage (GMH) is a major cause of brain damage in prematurity and has long-lasting neurological implications. The development of brain inflammation contributes to brain injury, leading to a lifetime of neurologic deficits. PAR-1 and 4 receptors are involved with inflammatory pathways after brain hemorrhage in adult models of stroke, of which cyclooxygenase-2 (COX-2) is a potential mediator. We therefore hypothesized a role for PAR-1, 4/ COX-2 signaling following GMH. Postnatal day 7 Sprague-Dawley rats were subjected to GMH induction, which entailed stereotactic collagenase infusion into the ganglionic eminence. Animals were euthanized at two time points: 72 h (short-term) or 4 weeks (long-term). Short-term COX-2 expression was evaluated in the context of PAR-1 (SCH-79797) and PAR-4 (P4pal10) inhibition. Pups in the long-term group were administered the selective COX-2 inhibitor (NS-398); and the neurobehavioral and pathological examinations were performed 4 weeks later. Pharmacological PAR-1, 4 antagonism normalized COX-2 expression following GMH and reduced hydrocephalus. Early inhibition of COX-2 by NS-398 improved long-term neurobehavioral outcomes. COX-2 signaling plays an important role in brain injury following neonatal GMH, possibly through upstream PAR-1, 4 receptor mechanisms.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Ballabh P (2010) Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 67:1–8
Aquilina K, Chakkarapani E, Love S, Thoresen M (2011) Neonatal rat model of intraventricular haemorrhage and post-haemorrhagic ventricular dilatation with long-term survival into adulthood. Neuropathol Appl Neurobiol 37:156–165
Chen Q, Zhang J, Guo J, Tang J, Tao Y, Li L, Feng H, Chen Z (2014) Chronic hydrocephalus and perihematomal tissue injury developed in a rat model of intracerebral hemorrhage with ventricular extension. Transl Stroke Res. doi:10.1007/s12975-014-0367-5
Zhao J, Chen Z, Xi G, Keep RF, Hua Y (2014) Deferoxamine attenuates acute hydrocephalus after traumatic brain injury in rats. Transl Stroke Res 5:586–594
Heron M, Sutton PD, Xu J, Ventura SJ, Strobino DM, Guyer B (2010) Annual summary of vital statistics: 2007. Pediatrics 125:4–15
Uria-Avellanal C, Robertson NJ (2014) Na(+)/H(+) exchangers and intracellular pH in perinatal brain injury. Transl Stroke Res 5:79–98
Whitelaw A (2001) Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions. Semin Neonatol 6:135–146
Gao F, Liu F, Chen Z, Hua Y, Keep RF, Xi G (2014) Hydrocephalus after intraventricular hemorrhage: the role of thrombin. J Cereb Blood Flow Metab 34:489–494
Cheng Y, Xi G, Jin H, Keep RF, Feng J, Hua Y (2014) Thrombin-induced cerebral hemorrhage: role of protease-activated receptor-1. Transl Stroke Res 5:472–475
Siler DA, Gonzalez JA, Wang RK, Cetas JS, Alkayed NJ (2014) Intracisternal administration of tissue plasminogen activator improves cerebrospinal fluid flow and cortical perfusion after subarachnoid hemorrhage in mice. Transl Stroke Res 5:227–237
Kataoka H, Hamilton JR, McKemy DD, Camerer E, Zheng YW, Cheng A, Griffin C, Coughlin SR (2003) Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells. Blood 102:3224–3231
Lo HM, Chen CL, Tsai YJ, Wu PH, Wu WB (2009) Thrombin induces cyclooxygenase-2 expression and prostaglandin E2 release via PAR1 activation and ERK1/2- and p38 MAPK-dependent pathway in murine macrophages. J Cell Biochem 108:1143–1152
Lekic T, Rolland W, Hartman R, Kamper J, Suzuki H, Tang J, Zhang JH (2011) Characterization of the brain injury, neurobehavioral profiles, and histopathology in a rat model of cerebellar hemorrhage. Exp Neurol 227:96–103
Manaenko A, Lekic T, Barnhart M, Hartman R, Zhang JH (2014) Inhibition of transforming growth factor-beta attenuates brain injury and neurological deficits in a rat model of germinal matrix hemorrhage. Stroke 45:828–834
Lekic T, Manaenko A, Rolland W, Krafft PR, Peters R, Hartman RE, Altay O, Tang J, Zhang JH (2012) Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalus. Exp Neurol 236:69–78
Leitzke AS, Rolland WB, Krafft PR, Lekic T, Klebe D, Flores JJ, Van Allen NR, Applegate RL 2nd, Zhang JH (2013) Isoflurane post-treatment ameliorates GMH- induced brain injury in neonatal rats. Stroke 44:3587–3590
Tang J, Liu J, Zhou C, Alexander JS, Nanda A, Granger DN, Zhang JH (2004) Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab 24:1133–1145
Fathali N, Ostrowski RP, Lekic T, Jadhav V, Tong W, Tang J, Zhang JH (2010) Cyclooxygenase-2 inhibition provides lasting protection against neonatal hypoxic-ischemic brain injury. Crit Care Med 38:572–578
Hughes RN (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev 28:497–505
Zhou Y, Fathali N, Lekic T, Tang J, Zhang JH (2009) Glibenclamide improves neurological function in neonatal hypoxia-ischemia in rats. Brain Res 1270:131–139
Tso MK, Macdonald RL (2014) Subarachnoid hemorrhage: a review of experimental studies on the microcirculation and the neurovascular unit. Transl Stroke Res 5:174–189
Marbacher S, Nevzati E, Croci D, Erhardt S, Muroi C, Jakob SM, Fandino J (2014) The rabbit shunt model of subarachnoid haemorrhage. Transl Stroke Res 5:669–680
Pluta RM, Bacher J, Skopets B, Hoffmann V (2014) A non-human primate model of aneurismal subarachnoid hemorrhage (SAH). Transl Stroke Res 5:681–691
Zhang YP, Cai J, Shields LB, Liu N, Xu XM, Shields CB (2014) Traumatic brain injury using mouse models. Transl Stroke Res 5:454–471
Wada K, Makino H, Shimada K, Shikata F, Kuwabara A, Hashimoto T (2014) Translational research using a mouse model of intracranial aneurysm. Transl Stroke Res 5:248–251
Strahle J, Garton HL, Maher C, Muraszko K, Keep R, Xi G (2012) Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res 3:25–38
Crews L, Wyss-Coray T, Masliah E (2004) Insights into the pathogenesis of hydrocephalus from transgenic and experimental animal models. Brain Pathol 14:312–316
Sorensen SS, Nygaard AB, Nielsen MY, Jensen K, Christensen T (2014) miRNA expression profiles in cerebrospinal fluid and blood of patients with acute ischemic stroke. Transl Stroke Res 5:711–718
Yamauchi T, Saito H, Ito M, Shichinohe H, Houkin K, Kuroda S (2014) Platelet lysate and granulocyte-colony stimulating factor serve safe and accelerated expansion of human bone marrow stromal cells for stroke therapy. Transl Stroke Res 5:701–710
Khanna A, Kahle KT, Walcott BP, Gerzanich V, Simard JM (2014) Disruption of ion homeostasis in the neurogliovascular unit underlies the pathogenesis of ischemic cerebral edema. Transl Stroke Res 5:3–16
Jiang X, Zhu S, Panetti TS, Bromberg ME (2008) Formation of tissue factor- factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells. Thromb Haemost 100:127–133
Gao C, Du H, Hua Y, Keep RF, Strahle J, Xi G (2014) Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage. J Cereb Blood Flow Metab 34:1070–1075
Reuter B, Rodemer C, Grudzenski S, Meairs S, Bugert P, Hennerici MG, Fatar M (2014) Effect of simvastatin on MMPs and TIMPs in human brain endothelial cells and experimental stroke. Transl Stroke Res. doi:10.1007/s12975-014-0381-7
Badaut J, Bix GJ (2014) Vascular neural network phenotypic transformation after traumatic injury: potential role in long-term sequelae. Transl Stroke Res 5:394–406
Acknowledgment
This study was partially supported by National Institutes of Health grant RO1 NS078755 (Dr. Zhang).
Disclosures
None
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Lekic, T. et al. (2016). Cyclooxygenase-2 Inhibition Provides Lasting Protection Following Germinal Matrix Hemorrhage in Premature Infant Rats. In: Applegate, R., Chen, G., Feng, H., Zhang, J. (eds) Brain Edema XVI. Acta Neurochirurgica Supplement, vol 121. Springer, Cham. https://doi.org/10.1007/978-3-319-18497-5_36
Download citation
DOI: https://doi.org/10.1007/978-3-319-18497-5_36
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-18496-8
Online ISBN: 978-3-319-18497-5
eBook Packages: MedicineMedicine (R0)