Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice

Journal of Neuroinflammation

Salvatore Cuzzocrea³  John L Wallace²  Giuseppe Bruschetta¹  Marika Cordaro¹  Irene Paterniti¹  Rosanna Di Paola¹  Akbar Ahmad¹  Emanuela Esposito¹  Michela Campolo¹ 

[1] Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, Messina, 31-98166, Italy;Inflammation Research Network, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4 N1, Alberta, Canada;Manchester Biomedical Research Centre, Manchester Royal Infirmary, School of Medicine, University of Manchester, 29 Grafton Street Manchester, Manchester, M13 9WU, UK

关键词: Neuroprotection;    Astrogliosis;    Nitrosative stress;    Infarct volume;    Infarct area;    Motor recovery;    Inflammation;    Neurotrophic factor;    Hydrogen sulfide;    Brain trauma;   

Others  :  1149928
DOI  :  10.1186/s12974-014-0196-1

 received in 2014-09-04, accepted in 2014-11-07,  发布年份 2014

【 摘 要 】

Background

Traumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed marked beneficial effects in an animal model of spinal cord injury, significantly enhancing recovery of motor function and reducing the secondary inflammation and tissue injury.

Methods

Here we evaluated the neuroprotective potential of ATB-346, a hydrogen sulfide-releasing derivative of naproxen, using the controlled cortical impact (CCI) injury model in mice, one of the most common models of TBI. Moreover, the aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of ATB-346 on inflammatory reaction associated with an experimental model of TBI. In these studies, TBI was induced in mice by CCI and mice were orally administered ATB-346, naproxen (both at 30 μmol/kg) or vehicle (dimethylsulfoxide:1% carboxymethylcellulose [5:95] suspension) one and six hours after brain trauma and once daily for 10 days.

Results

Results revealed that ATB-346 attenuated TBI-induced brain edema, suppressed TBI-induced neural cell death and improved neurological function. ATB-346 also significantly reduced the severity of inflammation and restored neurotrophic factors that characterized the secondary events of TBI.

Conclusions

These data demonstrate that ATB-346 can be efficacious in a TBI animal model by reducing the secondary inflammation and tissue injury. Therefore, ATB-346 could represent an interesting approach for the management of secondary damage following CNS diseases, counteracting behavioral changes and inflammatory process.

【 授权许可】

   
2014 Campolo et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Corrigan JD, Selassie AW, Orman JA: The epidemiology of traumatic brain injury. J Head Trauma Rehabil 2010, 25:72-80.
• [2]Rosenfeld JV, Maas AI, Bragge P, Morganti-Kossmann MC, Manley GT, Gruen RL: Early management of severe traumatic brain injury. Lancet 2012, 380:1088-1098.
• [3]Cernak I, Vink R, Zapple DN, Cruz MI, Ahmed F, Chang T, Fricke ST, Faden AI: The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats. Neurobiol Dis 2004, 17:29-43.
• [4]Anisimova IE, Salomatin EM, Pleteneva TV, Popov PI: Toxicity of non-steroid anti-inflammatory drugs. Sud Med Ekspert 2004, 47:37-41.
• [5]Geng B, Yang J, Qi Y, Zhao J, Pang Y, Du J, Tang C: H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun 2004, 313:362-368.
• [6]Zhao W, Zhang J, Lu Y, Wang R: The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 2001, 20:6008-6016.
• [7]Warenycia MW, Goodwin LR, Benishin CG, Reiffenstein RJ, Francom DM, Taylor JD, Dieken FP: Acute hydrogen sulfide poisoning. Demonstration of selective uptake of sulfide by the brainstem by measurement of brain sulfide levels. Biochem Pharmacol 1989, 38:973-981.
• [8]Kimura H: Hydrogen sulfide as a biological mediator. Antioxid Redox Signal 2005, 7:778-780.
• [9]Kimura H, Shibuya N, Kimura Y: Hydrogen sulfide is a signaling molecule and a cytoprotectant. Antioxid Redox Signal 2012, 17:45-57.
• [10]Wallace JL: Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol Sci 2007, 28:501-505.
• [11]Morgan K, Stevens EB, Shah B, Cox PJ, Dixon AK, Lee K, Pinnock RD, Hughes J, Richardson PJ, Mizuguchi K, Jackson AP: Beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc Natl Acad Sci U S A 2000, 97:2308-2313.
• [12]Campolo M, Esposito E, Ahmad A, Di Paola R, Wallace JL, Cuzzocrea S: A hydrogen sulfide-releasing cyclooxygenase inhibitor markedly accelerates recovery from experimental spinal cord injury. FASEB J 2013, 27:4489-4499.
• [13]Wallace JL, Caliendo G, Santagada V, Cirino G: Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br J Pharmacol 2010, 159:1236-1246.
• [14]Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M: A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009, 73:2061-2070.
• [15]Sullivan PG, Sebastian AH, Hall ED: Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. J Neurotrauma 2011, 28:311-318.
• [16]Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM: Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 1986, 17:1304-1308.
• [17]Schomacher M, Muller HD, Sommer C, Schwab S, Schabitz WR: Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia. Brain Res 2008, 1240:213-220.
• [18]Schabitz WR, Sommer C, Zoder W, Kiessling M, Schwaninger M, Schwab S: Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke 2000, 31:2212-2217.
• [19]Kawai T, Akira S: Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 2007, 13:460-469.
• [20]Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP: Traumatic spinal cord injury induces nuclear factor-kappaB activation. J Neurosci 1998, 18:3251-3260.
• [21]Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987, 162:156-159.
• [22]Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK: Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience 2005, 136:971-989.
• [23]Kimura Y, Kimura H: Hydrogen sulfide protects neurons from oxidative stress. FASEB J 2004, 18:1165-1167.
• [24]Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL: Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J 2006, 20:2118-2120.
• [25]Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S: Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology 2007, 132:261-271.
• [26]Li L, Salto-Tellez M, Tan CH, Whiteman M, Moore PK: GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free Radic Biol Med 2009, 47:103-113.
• [27]Polhemus DJ, Lefer DJ: Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res 2014, 114:730-737.
• [28]Kimura H: Hydrogen sulfide as a neuromodulator. Mol Neurobiol 2002, 26:13-19.
• [29]Blackler R, Syer S, Bolla M, Ongini E, Wallace JL: Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS One 2012, 7:e35196.
• [30]Wallace JL, Blackler RW, Chan MV, Da Silva GJ, Elsheikh W, Flannigan KL, Gamaniek I, Manko A, Wang L, Motta JP, Buret AG: Anti-inflammatory and cytoprotective actions of hydrogen sulfide: translation to therapeutics.Antioxid Redox Signal 2014.
• [31]Rhodes J: Peripheral immune cells in the pathology of traumatic brain injury? Curr Opin Crit Care 2011, 17:122-130.
• [32]Liao Y, Liu P, Guo F, Zhang ZY, Zhang Z: Oxidative burst of circulating neutrophils following traumatic brain injury in human. PLoS One 2013, 8:e68963.
• [33]DeKosky ST, Goss JR, Miller PD, Styren SD, Kochanek PM, Marion D: Upregulation of nerve growth factor following cortical trauma. Exp Neurol 1994, 130:173-177.
• [34]Goss JR, O’Malley ME, Zou L, Styren SD, Kochanek PM, DeKosky ST: Astrocytes are the major source of nerve growth factor upregulation following traumatic brain injury in the rat. Exp Neurol 1998, 149:301-309.
• [35]Mocchetti I, Wrathall JR: Neurotrophic factors in central nervous system trauma. J Neurotrauma 1995, 12:853-870.
• [36]Kim BT, Rao VL, Sailor KA, Bowen KK, Dempsey RJ: Protective effects of glial cell line-derived neurotrophic factor on hippocampal neurons after traumatic brain injury in rats. J Neurosurg 2001, 95:674-679.
• [37]Hermann DM, Kilic E, Kugler S, Isenmann S, Bahr M: Adenovirus-mediated glial cell line-derived neurotrophic factor (GDNF) expression protects against subsequent cortical cold injury in rats. Neurobiol Dis 2001, 8:964-973.
• [38]Shore PM, Jackson EK, Wisniewski SR, Clark RS, Adelson PD, Kochanek PM: Vascular endothelial growth factor is increased in cerebrospinal fluid after traumatic brain injury in infants and children. Neurosurgery 2004, 54:605-611. discussion 611–602
• [39]Pedersen MO, Larsen A, Pedersen DS, Stoltenberg M, Penkova M: Metallic gold treatment reduces proliferation of inflammatory cells, increases expression of VEGF and FGF, and stimulates cell proliferation in the subventricular zone following experimental traumatic brain injury. Histol Histopathol 2009, 24:573-586.
• [40]Cui X, Chopp M, Zacharek A, Ning R, Ding X, Roberts C, Chen J: Endothelial nitric oxide synthase regulates white matter changes via the BDNF/TrkB pathway after stroke in mice. PLoS One 2013, 8:e80358.
• [41]Lundblad C, Grande PO, Bentzer P: Hemodynamic and histological effects of traumatic brain injury in eNOS-deficient mice. J Neurotrauma 2009, 26:1953-1962.
• [42]Hall ED, Wang JA, Miller DM: Relationship of nitric oxide synthase induction to peroxynitrite-mediated oxidative damage during the first week after experimental traumatic brain injury. Exp Neurol 2012, 238:176-182.
• [43]Kondo K, Bhushan S, King AL, Prabhu SD, Hamid T, Koenig S, Murohara T, Predmore BL, Gojon G Sr, Gojon G Jr, Wang R, Karusula N, Nicholson CK, Calvert JW, Lefer DJ: H(2)S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation 2013, 127:1116-1127.
• [44]Kram L, Grambow E, Mueller-Graf F, Sorg H, Vollmar B: The anti-thrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases. Thromb Res 2013, 132:e112-e117.
• [45]Altaany Z, Yang G, Wang R: Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells. J Cell Mol Med 2013, 17:879-888.
• [46]Kamat PK, Kalani A, Givvimani S, Sathnur PB, Tyagi SC, Tyagi N: Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice. Neuroscience 2013, 252:302-319.