Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-α secretion after subacute cerebral ischemia

Wang,Jianping; Yang,Zhitang; Liu,Cong; Zhao,Yuanzheng; Chen,Yibing

doi:10.3892/ijmm.2012.1179

Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-α secretion after subacute cerebral ischemia

Authors:
- Jianping Wang
- Zhitang Yang
- Cong Liu
- Yuanzheng Zhao
- Yibing Chen
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Affiliations: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
Published online on: November 13, 2012 https://doi.org/10.3892/ijmm.2012.1179
Pages: 172-178

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Abstract

Microglia are the major immune cells in the central nervous system and play a key role in brain injury pathology. However, the role of activated microglia after subacute cerebral ischemia (SCI) remains unknown. To address this issue, we established a permanent middle cerebral artery occlusion (pMCAO) rat model and treated pMCAO rats with N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) (an inhibitor of microglial activation), or with vehicle alone. Finally, we determined the differences between the PJ34-and vehicle-treated rats with respect to neurological deficits, infarct volume, neuronal loss and the expression of CD11b (a marker of microglial activation), glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-α (TNF-α) at 1, 3 and 7 days after treatment. We found that the PJ34-treated rats had more severe neurological deficits and a larger infarct volume and exhibited a decreased CD11b expression, more neuronal loss, decreased expression of GDNF mRNA and protein but increased expression of TNF-α mRNA and protein compared with the vehicle-treated rats at 3 and 7 days after treatment. These results indicate that activated microglia provide a neuroprotective role through balancing GDNF and TNF-α expression following SCI.

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1	Lv M, Liu Y, Zhang J, et al: Roles of inflammation response in microglia cell through Toll-like receptors 2/interleukin-23/interleukin-17 pathway in cerebral ischemia/reperfusion injury. Neuroscience. 176:162–172. 2011. View Article : Google Scholar : PubMed/NCBI
2	Block ML and Hong JS: Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 76:77–98. 2005. View Article : Google Scholar : PubMed/NCBI
3	Liu B, Du L and Hong JS: Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther. 293:607–617. 2000.PubMed/NCBI
4	Napoli I and Neumann H: Protective effects of microglia in multiple sclerosis. Exp Neurol. 225:24–28. 2010. View Article : Google Scholar : PubMed/NCBI
5	Petersen MA and Dailey ME: Diverse microglial motility behaviors during clearance of dead cells in hippocampal slices. Glia. 46:195–206. 2004. View Article : Google Scholar : PubMed/NCBI
6	Lalancette-Hebert M, Gowing G, Simard A, Weng YC and Kriz J: Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 27:2596–2605. 2007. View Article : Google Scholar : PubMed/NCBI
7	Figueiredo C, Pais TF, Gomes JR and Chatterjee S: Neuron-microglia crosstalk up-regulates neuronal FGF-2 expression which mediates neuroprotection against excitotoxicity via JNK1/2. J Neurochem. 107:73–85. 2008. View Article : Google Scholar : PubMed/NCBI
8	Hamby AM, Suh SW, Kauppinen TM and Swanson RA: Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia-reperfusion. Stroke. 38:632–636. 2007. View Article : Google Scholar : PubMed/NCBI
9	Xi GM, Wang HQ, He GH, Huang CF and Wei GY: Evaluation of murine models of permanent focal cerebral ischemia. Chin Med J (Engl). 117:389–394. 2004.PubMed/NCBI
10	van der Kooij MA, Ohl F, Arndt SS, Kavelaars A, van Bel F and Heijnen CJ: Mild neonatal hypoxia-ischemia induces long-term motor- and cognitive impairments in mice. Brain Behav Immun. 24:850–856. 2010.PubMed/NCBI
11	Brooks SP and Dunnett SB: Tests to assess motor phenotype in mice: a user's guide. Nat Rev Neurosci. 10:519–529. 2009. View Article : Google Scholar : PubMed/NCBI
12	Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL and Bartkowski H: Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 17:472–476. 1986. View Article : Google Scholar : PubMed/NCBI
13	d'Avila JC, Lam TI, Bingham D, et al: Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation. 9:312012. View Article : Google Scholar : PubMed/NCBI
14	Hanisch UK and Kettenmann H: Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 10:1387–1394. 2007. View Article : Google Scholar : PubMed/NCBI
15	Frank-Cannon TC, Alto LT, McAlpine FE and Tansey MG: Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener. 4:472009. View Article : Google Scholar : PubMed/NCBI
16	Polazzi E and Monti B: Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog Neurobiol. 92:293–315. 2010. View Article : Google Scholar : PubMed/NCBI
17	Kaushal V and Schlichter LC: Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci. 28:2221–2230. 2008. View Article : Google Scholar : PubMed/NCBI
18	Hassa PO and Hottiger MO: The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci. 59:1534–1553. 2002. View Article : Google Scholar : PubMed/NCBI
19	Hassa PO, Buerki C, Lombardi C, Imhof R and Hottiger MO: Transcriptional coactivation of nuclear factor-kappaB-dependent gene expression by p300 is regulated by poly(ADP)-ribose polymerase-1. J Biol Chem. 278:45145–45153. 2003. View Article : Google Scholar : PubMed/NCBI
20	Kauppinen TM and Swanson RA: Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. J Immunol. 174:2288–2296. 2005. View Article : Google Scholar : PubMed/NCBI
21	Kauppinen TM, Higashi Y, Suh SW, Escartin C, Nagasawa K and Swanson RA: Zinc triggers microglial activation. J Neurosci. 28:5827–5835. 2008. View Article : Google Scholar : PubMed/NCBI
22	Ullrich O, Diestel A, Eyupoglu IY and Nitsch R: Regulation of microglial expression of integrins by poly(ADP-ribose) polymerase-1. Nat Cell Biol. 3:1035–1042. 2001. View Article : Google Scholar : PubMed/NCBI
23	Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T and Koistinaho J: Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA. 95:15769–15774. 1998. View Article : Google Scholar : PubMed/NCBI
24	Fan R, Xu F, Previti ML, et al: Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci. 27:3057–3063. 2007. View Article : Google Scholar : PubMed/NCBI
25	Mabley JG, Jagtap P, Perretti M, et al: Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase. Inflamm Res. 50:561–569. 2001. View Article : Google Scholar : PubMed/NCBI
26	Mabley JG, Horvath EM, Murthy KG, et al: Gender differences in the endotoxin-induced inflammatory and vascular responses: potential role of poly(ADP-ribose) polymerase activation. J Pharmacol Exp Ther. 315:812–820. 2005. View Article : Google Scholar : PubMed/NCBI
27	Gash DM, Zhang Z, Ovadia A, et al: Functional recovery in parkinsonian monkeys treated with GDNF. Nature. 380:252–255. 1996. View Article : Google Scholar : PubMed/NCBI
28	Li L, Wu W, Lin LF, Lei M, Oppenheim RW and Houenou LJ: Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor. Proc Natl Acad Sci USA. 92:9771–9775. 1995. View Article : Google Scholar : PubMed/NCBI
29	Wang Y, Lin SZ, Chiou AL, Williams LR and Hoffer BJ: Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex. J Neurosci. 17:4341–4348. 1997.PubMed/NCBI
30	Boscia F, Esposito CL, Di Crisci A, de Franciscis V, Annunziato L and Cerchia L: GDNF selectively induces microglial activation and neuronal survival in CA1/CA3 hippocampal regions exposed to NMDA insult through Ret/ERK signalling. PLoS One. 4:e64862009. View Article : Google Scholar : PubMed/NCBI
31	Hung SY, Liou HC and Fu WM: The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology. 58:321–329. 2010. View Article : Google Scholar : PubMed/NCBI
32	Sarit BS, Lajos G, Abraham D, Ron A and Sigal FB: Inhibitory role of kinins on microglial nitric oxide and tumor necrosis factor-alpha production. Peptides. 35:172–181. 2012. View Article : Google Scholar : PubMed/NCBI
33	Boucsein C, Zacharias R, Farber K, Pavlovic S, Hanisch UK and Kettenmann H: Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci. 17:2267–2276. 2003. View Article : Google Scholar : PubMed/NCBI
34	Nodin C, Zhu C, Blomgren K, Nilsson M and Blomstrand F: Decreased oxidative stress during glycolytic inhibition enables maintenance of ATP production and astrocytic survival. Neurochem Int. 61:291–301. 2012. View Article : Google Scholar : PubMed/NCBI
35	Lee GA, Lin CH, Jiang HH, Chao HJ, Wu CL and Hsueh CM: Microglia-derived glial cell line-derived neurotrophic factor could protect Sprague-Dawley rat astrocyte from in vitro ischemia-induced damage. Neurosci Lett. 356:111–114. 2004. View Article : Google Scholar : PubMed/NCBI
36	Beers DR, Henkel JS, Zhao W, Wang J and Appel SH: CD4⁺ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci USA. 105:15558–15563. 2008.PubMed/NCBI