Docosanoids Promote Neurogenesis and Angiogenesis, Blood-Brain Barrier Integrity, Penumbra Protection, and Neurobehavioral Recovery After Experimental Ischemic Stroke

Molecular Neurobiology - Tập 55 - Trang 7090-7106 - 2018
Ludmila Belayev1, Sung-Ha Hong1,2, Hemant Menghani1,3, Shawn J. Marcell1, Andre Obenaus4, Raul S. Freitas1,5, Larissa Khoutorova1, Veronica Balaszczuk1, Bokkyoo Jun1, Reinaldo B. Oriá1,5, Nicolas G. Bazan1
1Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, USA
2UT Health, McGovern Medical School, University of Texas Health Sciences Center at Houston, Houston, USA
3Department of Pediatrics, Hematology-Oncology, Louisiana State University Health New Orleans and Children’s Hospital of New Orleans, New Orleans, USA
4Department of Pediatrics, University of California, Irvine, Irvine, USA
5Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil

Tóm tắt

Docosahexaenoic acid (DHA) and neuroprotectin D1 (NPD1) are neuroprotective after experimental ischemic stroke. To explore underlying mechanisms, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo) and treated with DHA (5 mg/kg, IV) or NPD1 (5 μg/per rat, ICV) and vehicles 1 h after. Neuro-behavioral assessments was conducted on days 1, 2, and 3, and on week 1, 2, 3, or 4. BrdU was injected on days 4, 5, and 6, immunohistochemistry was performed on week 2 or 4, MRI on day 7, and lipidomic analysis at 4 and 5 h after onset of stroke. DHA improved short- and long-term behavioral functions and reduced cortical, subcortical, and total infarct volumes (by 42, 47, and 31%, respectively) after 2 weeks and reduced tissue loss by 50% after 4 weeks. DHA increased the number of BrdU+/Ki-67+, BrdU+/DCX+, and BrdU+/NeuN+ cells in the cortex, subventricular zone, and dentate gyrus and potentiated NPD1 synthesis in the penumbra at 5 h after MCAo. NPD1 improved behavior, reduced lesion volumes, protected ischemic penumbra, increased NeuN, GFAP, SMI-71-positive cells and vessels, axonal regeneration in the penumbra, and attenuated blood-brain barrier (BBB) after MCAo. We conclude that docosanoid administration increases neurogenesis and angiogenesis, activates NPD1 synthesis in the penumbra, and diminishes BBB permeability, which correlates to long-term neurobehavioral recovery after experimental ischemic stroke.

Tài liệu tham khảo

Mozaffarian D, Benjamin E, Go A, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després JP et al (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–e322. https://doi.org/10.1161/CIR.0000000000000152 Hirano T (2015) Evaluation of cerebral perfusion in patients undergoing intravenous recombinant tissue plasminogen activator thrombolysis. Neurol Med Chir 55:789–795. https://doi.org/10.2176/nmc.ra2015-0111 Jauch E, Saver J, Adams HJ et al (2013) Guidelines for the early management of patients with acute ischemic stroke. Stroke 44:870–947. https://doi.org/10.1161/STR.0b013e318284056a Font M, Arboix A, Krupinski J (2010) Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev 6:238–244. https://doi.org/10.2174/157340310791658802 Van Praaq H, Schinder A, Christie B et al (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034. https://doi.org/10.1038/4151030a Zhang R, Xue Y, Lu S et al (2006) Bcl-2 enhances neurogenesis and inhibits apoptosis of newborn neurons in adult rat brain following a transient middle cerebral artery occlusion. Neurobiol Dis 24:345–356. https://doi.org/10.1016/j.nbd.2006.07.012 Tobin M, Bonds J, Minshall R et al (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34:1573–1584. https://doi.org/10.1038/jcbfm.2014.130 Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases. Annu Rev Nutr 31:321–351. https://doi.org/10.1146/annurev.nutr.012809.104635 Kan I, Melamed E, Offen D, Green P (2007) Docosahexaenoic acid and arachidonic acid are fundamental supplements for the induction of neuronal differentiation. J Lipid Res 48:513–517. https://doi.org/10.1194/jlr.C600022-JLR200 Kawakita E, Hashimoto M, Shido O (2006) Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 139:991–997. https://doi.org/10.1016/j.neuroscience.2006.01.021 Crupi R, Marino A, Cuzzocrea S (2013) n-3 fatty acids: role in neurogenesis and neuroplasticity. Curr Med Chem 20:2953–2963. https://doi.org/10.2174/09298673113209990140 Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, Kim HY (2009) Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem 111:510–521. https://doi.org/10.1111/j.1471-4159.2009.06335.x TD Azad VA, Steinberg G (2016) Neurorestoration after stroke. Neurosurg Focus 40:e2. https://doi.org/10.3171/2016.2.FOCUS15637 Patel R, McMullan P (2017) Neuroprotection in the treatment of acute ischemic stroke. Prog Cardiovasc Dis 59:542–548. https://doi.org/10.1016/j.pcad.2017.04.005 Shapiro L (2017) Altered hippocampal neurogenesis during the first 7 days after a fluid percussion traumatic brain injury. Cell Transplant 26:1314–1318. https://doi.org/10.1177/0963689717714099 Wang X, Gao X, Michaelski S et al (2016) Traumatic brain injury severity affects neurogenesis in adult mouse hippocampus. J Neurotrauma 33:721–733. https://doi.org/10.1089/neu.2015.4097 Molina-Holgado E, Molina-Holgado F (2010) Mending the broken brain: neuroimmune interactions in neurogenesis. J Neurochem 114:1277–1290. https://doi.org/10.1111/j.1471-4159.2010.06849.x Hermann D, Chopp M (2012) Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol 11:369–380. https://doi.org/10.1016/S1474-4422(12)70039-X He K, Rimm E, Merchant A, Rosner BA, Stampfer MJ, Willett WC, Ascherio A (2002) Fish consumption and risk of stroke in men. JAMA 288:3130–3136. https://doi.org/10.1001/jama.288.24.3130 Bazan N (2009) Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer’s disease. J Lipid Res 50:400–405. https://doi.org/10.1194/jlr.R800068-JLR200 Simopoulos A (2008) The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med 233:674–688. https://doi.org/10.3181/0711-MR-311 Zhang W, Wang H, Zhang H, Leak RK, Shi Y, Hu X, Gao Y, Chen J (2015) Dietary supplementation with omega-3 polyunsaturated fatty acids robustly promotes neurovascular restorative dynamics and improves neurological functions after stroke. Exp Neurol 272:170–180. https://doi.org/10.1016/j.expneurol.2015.03.005 Pu H, Jiang X, Hu X, Xia J, Hong D, Zhang W, Gao Y, Chen J et al (2016) Delayed docosahexaenoic acid treatment combined with dietary supplementation of omega-3 fatty acids promotes long-term neurovascular restoration after ischemic stroke. Transl Stroke Res 7:521–534. https://doi.org/10.1007/s12975-016-0498-y Dyall S (2015) Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci 7:52. https://doi.org/10.3389/fnagi.2015.00052 Dagai L, Peri-Naor R, Birk R (2009) Docosahexaenoic acid significantly stimulates immediate early response genes and neurite outgrowth. Neurochem Res 34:867–875. https://doi.org/10.1007/s11064-008-9845-z Calderon F, Kim H (2004) Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem 90:979–988. https://doi.org/10.1111/j.1471-4159.2004.02520.x Sakayori N, Maekawa M, Numayama-Tsuruta K, Katura T, Moriya T, Osumi N (2011) Distinctive effects of arachidonic acid and docosahexaenoic acid on neural stem/progenitor cells. Genes Cells 16:778–790. https://doi.org/10.1111/j.1365-2443.2011.01527.x Hashimoto M, Hossain S, Al Mamun A et al (2017) Docosahexaenoic acid: one molecule diverse functions. Crit Rev Biotechnol 37:579–597. https://doi.org/10.1080/07388551.2016.1207153 Belayev L, Khoutorova L, Atkins K et al (2011) Docosahexaenoic acid therapy of experimental ischemic stroke. Transl Stroke Res 2:33–41. https://doi.org/10.1007/s12975-010-0046-0 Eady T, Belayev L, Khoutorova L et al (2012) Docosahexaenoic acid signaling modulates cell survival in experimental ischemic stroke penumbra and initiates long-term repair in young and aged rats. PLoS One 7:e46151. https://doi.org/10.1371/journal.pone.0046151 Hong S, Khoutorova L, Bazan N, Belayev L (2015) Docosahexaenoic acid improves behavior and attenuates blood-brain barrier injury induced by focal cerebral ischemia in rats. Exp Transl Stroke Med 7:3. https://doi.org/10.1186/s13231-014-0012-0 Serhan C, Dalli J, Colas R et al (2015) Protectins and maresins: new pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim Biophys Acta 1851:397–413. https://doi.org/10.1016/j.bbalip.2014.08.006 Marcheselli V, Hong S, Lukiw W et al (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278:43807–43817. https://doi.org/10.1074/jbc.M305841200 Mukherjee P, Marcheselli V, Serhan C, Bazan N (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 101:8491–8496. https://doi.org/10.1073/pnas.0402531101 Asatryan A, Bazan N (2017) Molecular mechanisms of signaling via the docosanoid neuroprotection D1 for cellular homeostasis and neuroprotection. J Biol Chem 292:12390–12397. https://doi.org/10.1074/jbc.R117.783076 Belayev L, Mukherjee P, Balaszczuk V et al (2017) Neuroprotectin D1 upregulates Iduna expression and provides protection in cellular uncompensated oxidative stress and in experimental ischemic stroke. Cell Death Differ 24:1091–1099. https://doi.org/10.1038/cdd.2017.55 Calandria J, Asatryan A, Balaszczuk V et al (2015) NPD1-mediated stereoselective regulation of BIRC3 expression through cREL is decisive for neuronal cell survival. Cell Death Differ 22:1363–1377. https://doi.org/10.1038/cdd.2014.233 Belayev L, Alonso O, Busto R et al (1996) Middle cerebral artery occlusion in the rat by intraluminal suture: neurological and pathological evaluation of an improved model. Stroke 27:1616–1622. https://doi.org/10.1161/01.STR.27.9.1616 Belayev L, Khoutorova L, Atkins K, Bazan N (2009) Robust docosahexaenoic acid-mediated neuroprotection in a rat model of transient, focal cerebral ischemia. Stroke 40:3121–3126. https://doi.org/10.1161/STROKEAHA.109.555979 Yao C, Zhang J, Chen F, Lin Y (2013) Neuroprotectin D1 attenuates brain damage induced by transient middle cerebral artery occlusion in rats through TRPC6/CREB pathways. Mol Med Rep 8:543–550. https://doi.org/10.3892/mmr.2013.1543 Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970. https://doi.org/10.1038/nm747 Thiyagarajan M, Fernandez J, Lane S et al (2008) Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J Neurosci 28:12788–12797. https://doi.org/10.1523/JNEUROSCI.3485-08.2008 Zhang Y, Pardridge W (2006) Blood–brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Res 1111:227–229. https://doi.org/10.1016/j.brainres.2006.07.005 Thompson S, Gibson T, Thompson B et al (2006) Relationship of calpain-mediated proteolysis to the expression of axonal and synaptic plasticity markers following traumatic brain injury in mice. Exp Neurol 201:253–265. https://doi.org/10.1016/j.expneurol.2006.04.01 Belayev L, Khoutorova L, Zhao K et al (2009) A novel neurotrophic therapeutic strategy for experimental stroke. Brain Res 1280:117–123. https://doi.org/10.1016/j.brainres.2009.05.030 Haley M, Lawrence C (2017) The blood–brain barrier after stroke: structural studies and the role of transcytotic vesicles. J Cereb Blood Flow Metab 37:456–470. https://doi.org/10.1177/0271678X16629976 Readnower R, Chavko M, Adeeb S et al (2010) Increase in blood–brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury. J Neurosci Res 88:3530–3539. https://doi.org/10.1002/jnr.22510 Obenaus A, Dilmac N, Tone B, Tian HR, Hartman R, Digicaylioglu M, Snyder EY, Ashwal S (2011) Long-term magnetic resonance imaging of stem cells in neonatal ischemic injury. Ann Neurol 69:282–291. https://doi.org/10.1002/ana.22168 Bazan N, Eady T, Khoutorova L et al (2012) Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp Neurol 236:122–130. https://doi.org/10.1016/j.expneurol.2012.04.007 von Bohlen Und Halbach O (2007) Immunohistological markers for staging neurogenesis in adult hippocampus. Cell Tissue Res 329:409–420 . doi: https://doi.org/10.1007/s00441-007-0432-4 von Bohlen Und Halbach O (2011) Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res 345:1–19 . doi: https://doi.org/10.1007/s00441-011-1196-4 Rao M, Shetty A (2004) Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur J Neurosci 19:234–246. https://doi.org/10.1111/j.0953-816X.2003.03123.x Bazan N (2005) Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathol 15:159–166. https://doi.org/10.1111/j.1750-3639.2005.tb00513.x Bazan N (2007) Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: The proctor lecture. Invest Ophthalmol Vis Sci 48:4866–4881. https://doi.org/10.1167/iovs.07-0918 Donnan G, Baron J, Ma H, Davis S (2009) Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol 8:261–269. https://doi.org/10.1016/S1474-4422(09)70041-9 Ebinger M, De Silva D, Christensen S et al (2009) Imaging the penumbra - strategies to detect tissue at risk after ischemic stroke. J Clin Neurosci 16:178–187. https://doi.org/10.1016/j.jocn.2008.04.002 Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808. https://doi.org/10.1038/nm.2399 Mogoantă L, Pirici D, Pop O, Bălşeanu AT, Rolea E, Dahnovici RM (2010) Study of vascular microdensity in areas of cerebral ischemia on experimental model. Romanian J Morphol Embryol 51:725–731 Belayev L, Busto R, Zhao W, Ginsberg M (1996) Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res 739:88–96. https://doi.org/10.1016/S0006-8993(96)00815-3 Yang Y, Rosenberg G (2011) Blood–brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 42:3323–3328. https://doi.org/10.1161/STROKEAHA.110.608257 Rosenberg G (2012) Neurological diseases in relation to the blood–brain barrier. J Cereb Blood Flow Metab 32:1139–1151. https://doi.org/10.1038/jcbfm.2011.197