Docosahexaenoic acid attenuates the early inflammatory response following spinal cord injury in mice: in-vivo and in-vitro studies

Journal of Neuroinflammation

Salvatore Cuzzocrea²  Adina T Michael-Titus¹  John V Priestley¹  Ping Yip¹  Stacy Gladman¹  Emanuela Esposito²  Rosanna Di Paola²  Daniela Impellizzeri²  Irene Paterniti² 

[1] Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK;Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 98166 Messina, Italy

关键词: Spinal cord injury;    Oxidative stress;    Omega-3;    Inflammation;    DHA;   

Others  :  834533
DOI  :  10.1186/1742-2094-11-6

 received in 2013-10-28, accepted in 2013-12-30,  发布年份 2014

【 摘 要 】

Background

Two families of polyunsaturated fatty acid (PUFA), omega-3 (ω-3) and omega-6 (ω-6), are required for physiological functions. The long chain ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have significant biological effects. In particular, DHA is a major component of cell membranes in the brain. It is also involved in neurotransmission. Spinal cord injury (SCI) is a highly devastating pathology that can lead to catastrophic dysfunction, with a significant reduction in the quality of life. Previous studies have shown that EPA and DHA can exert neuroprotective effects in SCI in mice and rats. The aim of this study was to analyze the mechanism of action of ω-3 PUFAs, such as DHA, in a mouse model of SCI, with a focus on the early pathophysiological processes.

Methods

In this study, SCI was induced in mice by the application of an aneurysm clip onto the dura mater via a four-level T5 to T8 laminectomy. Thirty minutes after compression, animals received a tail vein injection of DHA at a dose of 250 nmol/kg. All animals were killed at 24 h after SCI, to evaluate various parameters implicated in the spread of the injury.

Results

Our results in this in-vivo study clearly demonstrate that DHA treatment reduces key factors associated with spinal cord trauma. Treatment with DHA significantly reduced: (1) the degree of spinal cord inflammation and tissue injury, (2) pro-inflammatory cytokine expression (TNF-α), (3) nitrotyrosine formation, (4) glial fibrillary acidic protein (GFAP) expression, and (5) apoptosis (Fas-L, Bax, and Bcl-2 expression). Moreover, DHA significantly improved the recovery of limb function.

Furthermore, in this study we evaluated the effect of oxidative stress on dorsal root ganglion (DRG) cells using a well-characterized in-vitro model. Treatment with DHA ameliorated the effects of oxidative stress on neurite length and branching.

Conclusions

Our results, in vivo and in vitro, clearly demonstrate that DHA treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

【 授权许可】

   
2014 Paterniti et al.; licensee BioMed Central Ltd.

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【 参考文献 】

• [1]Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ: A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 2003, 103:249-257.
• [2]Cardenas DD, Hoffman JM, Kirshblum S, McKinley W: Etiology and incidence of rehospitalization after traumatic spinal cord injury: a multicenter analysis. Arch Phys Med Rehabil 2004, 85:1757-1763.
• [3]Popovich PG, Wei P, Stokes BT: Cellular inflammatory response after spinal cord injury in Sprague–Dawley and Lewis rats. J Comp Neurol 1997, 377:443-464.
• [4]Streit WJ, Graeber MB, Kreutzberg GW: Functional plasticity of microglia: a review. Glia 1988, 1:301-307.
• [5]Schwartz M, Moalem G, Leibowitz-Amit R, Cohen IR: Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci 1999, 22:295-299.
• [6]Donnelly DJ, Popovich PG: Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol 2008, 209:378-388.
• [7]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8:752-758.
• [8]Amar AP, Levy ML: Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury. Neurosurgery 1999, 44:1027-1039. Discussion 1039–1040
• [9]Silver J, Miller JH: Regeneration beyond the glial scar. Nat Rev Neurosci 2004, 5:146-156.
• [10]Calon F, Cole G: Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fatty Acids 2007, 77:287-293.
• [11]Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM: Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-β and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci 2007, 27:4385-4395.
• [12]Ward RE, Huang W, Curran OE, Priestley JV, Michael-Titus AT: Docosahexaenoic acid prevents white matter damage after spinal cord injury. J Neurotrauma 2010, 27:1769-1780.
• [13]Hall JC, Priestley JV, Perry VH, Michael-Titus AT: Docosahexaenoic acid, but not eicosapentaenoic acid, reduces the early inflammatory response following compression spinal cord injury in the rat. J Neurochem 2012, 121:738-750.
• [14]Huang WL, King VR, Curran OE, Dyall SC, Ward RE, Lal N, Priestley JV, Michael-Titus AT: A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain 2007, 130:3004-3019.
• [15]King VR, Huang WL, Dyall SC, Curran OE, Priestley JV, Michael-Titus AT: Omega-3 fatty acids improve recovery, whereas omega-6 fatty acids worsen outcome, after spinal cord injury in the adult rat. J Neurosci 2006, 26:4672-4680.
• [16]Lim SN, Huang W, Hall JC, Michael-Titus AT, Priestley JV: Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid. Exp Neurol 2013, 239:13-27.
• [17]Lim SN, Huang W, Hall JC, Ward RE, Priestley JV, Michael-Titus AT: The acute administration of eicosapentaenoic acid is neuroprotective after spinal cord compression injury in rats. Prostaglandins Leukot Essent Fatty Acids 2010, 83:193-201.
• [18]Rivlin AS, Tator CH: Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg Neurol 1978, 10:38-43.
• [19]Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, Popovich PG: Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma 2006, 23:635-659.
• [20]Ceruti S, Villa G, Genovese T, Mazzon E, Longhi R, Rosa P, Bramanti P, Cuzzocrea S, Abbracchio MP: The P2Y-like receptor GPR17 as a sensor of damage and a new potential target in spinal cord injury. Brain 2009, 132:2206-2218.
• [21]Shea TB: Technical report. An inexpensive densitometric analysis system using a Macintosh computer and a desktop scanner. Biotechniques 1994, 16:1126-1128.
• [22]Lang-Lazdunski L, Blondeau N, Jarretou G, Lazdunski M, Heurteaux C: Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats. J Vasc Surg 2003, 38:564-575.
• [23]Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP: Traumatic spinal cord injury induces nuclear factor-κB activation. J Neurosci 1998, 18:3251-3260.
• [24]Gavazzi I, Kumar RD, McMahon SB, Cohen J: Growth responses of different subpopulations of adult sensory neurons to neurotrophic factors in vitro. Eur J Neurosci 1999, 11:3405-3414.
• [25]Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, Mori T, Gotz M: Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain. Proc Natl Acad Sci USA 2008, 105:3581-3586.
• [26]Bracken MB: Methylprednisolone in the management of acute spinal cord injuries. Med J Aust 1990, 153:368.
• [27]La Rosa G, Cardali S, Genovese T, Conti A, Di Paola R, La Torre D, Cacciola F, Cuzzocrea S: Inhibition of the nuclear factor-κB activation with pyrrolidine dithiocarbamate attenuating inflammation and oxidative stress after experimental spinal cord trauma in rats. J Neurosurg Spine 2004, 1:311-321.
• [28]Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D, Steward W, Dennison A: The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer 2009, 45:2077-2086.
• [29]Verma IM: Nuclear factor (NF)-κB proteins: therapeutic targets. Ann Rheum Dis 2004, 63(Suppl 2):ii57-ii61.
• [30]Paterniti I, Genovese T, Mazzon E, Crisafulli C, Di Paola R, Galuppo M, Bramanti P, Cuzzocrea S: Liver X receptor agonist treatment regulates inflammatory response after spinal cord trauma. J Neurochem 2010, 112:611-624.
• [31]Bao F, Liu D: Peroxynitrite generated in the rat spinal cord induces apoptotic cell death and activates caspase-3. Neuroscience 2003, 116:59-70.
• [32]Gladman SJ, Ward RE, Michael-Titus AT, Knight MM, Priestley JV: The effect of mechanical strain or hypoxia on cell death in subpopulations of rat dorsal root ganglion neurons in vitro. Neuroscience 2010, 171:577-587.