Neuregulin-1 inhibits neuroinflammatory responses in a rat model of organophosphate-nerve agent-induced delayed neuronal injury
Tóm tắt
Neuregulin-1 (NRG-1) has been shown to act as a neuroprotectant in animal models of nerve agent intoxication and other acute brain injuries. We recently demonstrated that NRG-1 blocked delayed neuronal death in rats intoxicated with the organophosphate (OP) neurotoxin diisopropylflurophosphate (DFP). It has been proposed that inflammatory mediators are involved in the pathogenesis of OP neurotoxin-mediated brain damage. We examined the influence of NRG-1 on inflammatory responses in the rat brain following DFP intoxication. Microglial activation was determined by immunohistchemistry using anti-CD11b and anti-ED1 antibodies. Gene expression profiling was performed with brain tissues using Affymetrix gene arrays and analyzed using the Ingenuity Pathway Analysis software. Cytokine mRNA levels following DFP and NRG-1 treatment was validated by real-time reverse transcription polymerase chain reaction (RT-PCR). DFP administration resulted in microglial activation in multiple brain regions, and this response was suppressed by treatment with NRG-1. Using microarray gene expression profiling, we observed that DFP increased mRNA levels of approximately 1,300 genes in the hippocampus 24 h after administration. NRG-1 treatment suppressed by 50% or more a small fraction of DFP-induced genes, which were primarily associated with inflammatory responses. Real-time RT-PCR confirmed that the mRNAs for pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) were significantly increased following DFP exposure and that NRG-1 significantly attenuated this transcriptional response. In contrast, tumor necrosis factor α (TNFα) transcript levels were unchanged in both DFP and DFP + NRG-1 treated brains relative to controls. Neuroprotection by NRG-1 against OP neurotoxicity is associated with the suppression of pro-inflammatory responses in brain microglia. These findings provide new insight regarding the molecular mechanisms involved in the neuroprotective role of NRG-1 in acute brain injuries.
Tài liệu tham khảo
Jett DA. Neurological aspects of chemical terrorism. Ann Neurol. 2007;61(1):9–13.
Collombet JM. Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects. Toxicol Appl Pharmacol. 2011;255(3):229–41.
UN, United Nations Secretary General Report: United Nations mission to investigate allegations of the use of chemical weapons in the Syrian Arab Republic. Report on the alleged use of chemical weapons in the Ghouta Area of Damascus on 21 August 2013. http://www.un.org/disarmament/content/slideshow/Secretary_General_Report_of_CW_Investigation.pdf. 2013.
Newmark J. The birth of nerve agent warfare: lessons from Syed Abbas Foroutan. Neurology. 2004;62(9):1590–6.
Okudera H. Clinical features on nerve gas terrorism in Matsumoto. J Clin Neurosci. 2002;9(1):17–21.
Okumura T, Hisaoka T, Yamada A, Naito T, Isonuma H, Okumura S, et al. The Tokyo subway sarin attack - lessons learned. Toxicol Appl Pharmacol. 2005;207(2 Suppl):471–6.
Yanagisawa N, Morita H, Nakajima T. Sarin experiences in Japan: acute toxicity and long-term effects. J Neurol Sci. 2006;249(1):76–85.
Hoffman A, Eisenkraft A, Finkelstein A, Schein O, Rotman E, Dushnitsky T. A decade after the Tokyo sarin attack: a review of neurological follow-up of the victims. Mil Med. 2007;172(6):607–10.
Li Y, Lein PJ, Liu C, Bruun DA, Giulivi C, Ford GD, et al. Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury. Toxicol Appl Pharmacol. 2012;262(2):194–204.
Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993;72(5):801–15.
Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 1993;362:312–8.
Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, et al. Identification of heregulin, a specific activator of p185erbB2. Science. 1992;256(5060):1205–10.
Wen D, Peles E, Cupples R, Suggs SV, Bacus SS, Luo Y, et al. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992;69(3):559–72.
Ho WH, Armanini MP, Nuijens A, Phillips HS, Osheroff PL. Sensory and motor neuron-derived factor. A novel heregulin variant highly expressed in sensory and motor neurons. J Biol Chem. 1995;270(44):26722.
Deshpande LS, Carter DS, Blair RE, DeLorenzo RJ. Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate. Toxicol Sci. 2010;116(2):623–31.
Lemercier G, Carpentier P, Sentenac-Roumanou H, Morelis P. Histological and histochemical changes in the central nervous system of the rat poisoned by an irreversible anticholinesterase organophosphorus compound. Acta Neuropathol (Berl). 1983;61(2):123–9.
McDonough Jr JH, McLeod Jr CG, Nipwoda MT. Direct microinjection of soman or VX into the amygdala produces repetitive limbic convulsions and neuropathology. Brain Res. 1987;435(1–2):123–37.
McLeod Jr CG, Singer AW, Harrington DG. Acute neuropathology in soman poisoned rats. Neurotoxicology. 1984;5(2):53–7.
Petras JM. Neurology and neuropathology of Soman-induced brain injury: an overview. J Exp Anal Behav. 1994;61(2):319–29.
Zimmer LA, Ennis M, Shipley MT. Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions. J Comp Neurol. 1997;378(4):482–92.
Collombet JM, Four E, Bernabe D, Masqueliez C, Burckhart MF, Baille V, et al. Soman poisoning increases neural progenitor proliferation and induces long-term glial activation in mouse brain. Toxicology. 2005;208(3):319–34.
Dhote F, Peinnequin A, Carpentier P, Baille V, Delacour C, Foquin A, et al. Prolonged inflammatory gene response following soman-induced seizures in mice. Toxicology. 2007;238(2–3):166–76.
Dillman 3rd JF, Phillips CS, Kniffin DM, Tompkins CP, Hamilton TA, Kan RK. Gene expression profiling of rat hippocampus following exposure to the acetylcholinesterase inhibitor soman. Chem Res Toxicol. 2009;22(4):633–8.
Chapman S, Kadar T, Gilat E. Seizure duration following sarin exposure affects neuro-inflammatory markers in the rat brain. Neurotoxicology. 2006;27(2):277–83.
Johnson EA, Kan RK. The acute phase response and soman-induced status epilepticus: temporal, regional and cellular changes in rat brain cytokine concentrations. J Neuroinflammation. 2010;7:40.
Svensson I, Waara L, Johansson L, Bucht A, Cassel G. Soman-induced interleukin-1 beta mRNA and protein in rat brain. Neurotoxicology. 2001;22(3):355–62.
Williams AJ, Berti R, Yao C, Price RA, Velarde LC, Koplovitz I, et al. Central neuro-inflammatory gene response following soman exposure in the rat. Neurosci Lett. 2003;349(3):147–50.
Shih T, Whalley CE, Valdes JJ. A comparison of cholinergic effects of HI-6 and pralidoxime-2-chloride (2-PAM) in soman poisoning. Toxicol Lett. 1991;55(2):131–47.
Kim Y-B, Hur G, Shin S, Sok D, Kang J, Lee Y. Organophosphate-induced brain injuries: delayed apoptosis mediated by nitric oxide. Environ Toxicol Pharm. 1999;7:147–52.
Li Y, Lein PJ, Liu C, Bruun DA, Tewolde T, Ford G, et al. Spatiotemporal pattern of neuronal injury induced by DFP in rats: a model for delayed neuronal cell death following acute OP intoxication. Toxicol Appl Pharmacol. 2011;253(3):261–9.
De Sarro G, Di Paola ED, De Sarro A, Vidal MJ. L-arginine potentiates excitatory amino acid-induced seizures elicited in the deep prepiriform cortex. Eur J Pharmacol. 1993;230(2):151–8.
Li Y, Xu Z, Ford GD, Croslan DR, Cairobe T, Li Z, et al. Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia. Brain Res. 2007;1184:277–83.
Colton CA. Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol. 2009;4(4):399–418.
Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17(7):796–808.
Raveh L, Brandeis R, Gilat E, Cohen G, Alkalay D, Rabinovitz I, et al. Anticholinergic and antiglutamatergic agents protect against soman-induced brain damage and cognitive dysfunction. Toxicol Sci. 2003;75(1):108–16.
Spradling KD, Lumley LA, Robison CL, Meyerhoff JL, Dillman 3rd JF. Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures. J Neuroinflammation. 2011;8:83.
Kaplan M, Aviram M. Oxidized low density lipoprotein: Atherogenic and proinflammatory characteristics during macrophage foam cell formation. An inhibitory role for nutritional antioxidants and serum paraoxonase. Clin Chem Lab Med. 1999;37(8):777–87.
Moore KW, de Waal MR, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.
Solomon W, Wilson NO, Anderson L, Pitts S, Patrickson J, Liu M, et al. Neuregulin-1 attenuates mortality associated with experimental cerebral malaria. J Neuroinflammation. 2014;11:9.
Dimayuga FO, Ding Q, Keller JN, Marchionni MA, Seroogy KB, Bruce-Keller AJ. The neuregulin GGF2 attenuates free radical release from activated microglial cells. J Neuroimmunol. 2003;136(1–2):67–74.
Xu Z, Ford GD, Croslan DR, Jiang J, Gates A, Allen R, et al. Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. Neurobiol Dis. 2005;19(3):461–70.
Calvo M, Zhu N, Grist J, Ma Z, Loeb JA, Bennett DL. Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway. Glia. 2011;59(4):554–68.
Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA, et al. Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci. 2010;30(15):5437–50.
Clement CM, Thomas LK, Mou Y, Croslan DR, Gibbons GH, Ford BD. Neuregulin-1 attenuates neointimal formation following vascular injury and inhibits the proliferation of vascular smooth muscle cells. J Vasc Res. 2007;44(4):303–12.
Watanabe T, Sato K, Itoh F, Iso Y. Pathogenic involvement of heregulin-beta(1) in anti-atherogenesis. Regul Pept. 2012;175(1–3):11–4.
Xu G, Watanabe T, Iso Y, Koba S, Sakai T, Nagashima M, et al. Preventive effects of heregulin-beta1 on macrophage foam cell formation and atherosclerosis. Circ Res. 2009;105(5):500–10.
Berti R, Williams AJ, Moffett JR, Hale SL, Velarde LC, Elliott PJ, et al. Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. J Cereb Blood Flow Metab. 2002;22(9):1068–79.
Shohami E, Novikov M, Bass R, Yamin A, Gallily R. Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue. J Cereb Blood Flow Metab. 1994;14(4):615–9.
Shyu WC, Lin SZ, Chiang MF, Yang HI, Thajeb P, Li H. Neuregulin-1 reduces ischemia-induced brain damage in rats. Neurobiol Aging. 2004;25(7):935–44.
Xu Z, Jiang J, Ford G, Ford BD. Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun. 2004;322(2):440–6.
Iaci JF, Ganguly A, Finklestein SP, Parry TJ, Ren J, Saha S, et al. Glial growth factor 2 promotes functional recovery with treatment initiated up to 7 days after permanent focal ischemic stroke. Neuropharmacology. 2010;59(7–8):640–9.
Xu Z, Croslan DR, Harris AE, Ford GD, Ford BD. Extended therapeutic window and functional recovery after intraarterial administration of neuregulin-1 after focal ischemic stroke. J Cereb Blood Flow Metab. 2006;26(4):527–35.
Gao R, Zhang J, Cheng L, Wu X, Dong W, Yang X, et al. A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J Am Coll Cardiol. 2010;55(18):1907–14.
Jabbour A, Hayward CS, Keogh AM, Kotlyar E, McCrohon JA, England JF, et al. Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail. 2011;13(1):83–92.
Lok J, Wang H, Murata Y, Zhu HH, Qin T, Whalen MJ, et al. Effect of neuregulin-1 on histopathological and functional outcome after controlled cortical impact in mice. J Neurotrauma. 2007;24(12):1817–22.