Minocycline attenuates microglial response and reduces neuronal death after cardiac arrest and cardiopulmonary resuscitation in mice

Abstract

The possible role of minocycline in microglial activation and neuronal death after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in mice was investigated in this study. The mice were given potassium chloride to stop the heart beating for 8 min to achieve CA, and they were subsequently resuscitated with epinephrine and chest compressions. Forty adult C57BL/6 male mice were divided into 4 groups (n=10 each): sham-operated group, CA/CPR group, CA/CPR+minocycline group, and CA/CPR+vehicle group. Animals in the latter two groups were intraperitoneally injected with minocycline (50 mg/kg) or vehicle (normal saline) 30 min after recovery of spontaneous circulation (ROSC). Twenty-four h after CA/CPR, the brains were removed for histological evaluation of the hippocampus. Microglial activation was evaluated by detecting the expression of ionized calcium-binding adapter molecule-1 (Iba1) by immunohistochemistry. Neuronal death was analyzed by hematoxylin and eosin (H&E) staining and the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that the neuronal death was aggravated, most microglia were activated and TNF-α levels were enhanced in the hippocampus CA1 region of mice subjected to CA/CPR as compared with those in the sham-operated group (P<0.05). Administration with minocycline 30 min after ROSC could significantly decrease the microglial response, TNF-α levels and neuronal death (P<0.05). It was concluded that early administration with minocycline has a strong therapeutic potential for CA/CPR-induced brain injury.

Keywords

cardiac arrest / cardiopulmonary resuscitation / minocycline / microglia

References

[1] RosamondW, FlegalK, FridayG, et al. . Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and stroke statistics subcommittee. Circulation, 2007, 115(5): e69-e171 PMID: 17194875

[2] ReaTD, EisenbergMS, BeckerLJ, et al. . Temporal trends in sudden cardiac arrest: a 25-year emergency medical services perspective. Circulation, 2003, 107(22): 2780-2785 PMID: 12756155

[3] CrepelV, EpszteinJ, Ben-AriY. Ischemia induces short- and long-term remodeling of synaptic activity in the hippocampus. J Cell Mol Med, 2003, 7(4): 401-407 PMID: 14754508

[4] YenariMA, KauppinenTM, SwansonRA. Microglial activation in stroke: therapeutic targets. Neurotherapeutics, 2010, 7(4): 378-391 PMID: 20880502

[5] TangM, AlexanderH, ClarkRS, et al. . Minocycline reduces neuronal death and attenuates microglial response after pediatric asphyxial cardiac arrest. J Cereb Blood Flow Metab, 2010, 30(1): 119-129 PMCID: 2949095 PMID: 19756023

[6] NormanGJ, MorrisJS, KarelinaK, et al. . Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic alpha7 nicotinic receptors. J Neurosci, 2011, 31(9): 3446-3452 PMCID: 3758544 PMID: 21368056

[7] SutherlandBA, MinnerupJ, BalamiJS, et al. . Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke, 2012, 7(5): 407-418 PMID: 22394615

[8] PlaneJM, ShenY, PleasureDE, et al. . Prospects for minocycline neuroprotection. Arch Neurol, 2010, 67(12): 1442-1448 PMCID: 3127230 PMID: 20697034

[9] HodaMN, LiW, AhmadA, et al. . Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med, 2011, 3(1): 16 PMCID: 3287111 PMID: 22177314

[10] AllenD, NakayamaS, KuroiwaM, et al. . SK2 channels are neuroprotective for ischemia-induced neuronal cell death. J Cereb Blood Flow Metab, 2011, 31(12): 2302-2312 PMCID: 3323193 PMID: 21712833

[11] Lalancette-HébertM, SwarupV, BeaulieuJM, et al. . Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. J Neurosci, 2012, 32(30): 10383-10395 PMID: 22836271

[12] Prassk, MeiselC, HoflichC, et al. . Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by post stroke T helper cell type 1-like immunostimulation. J Exp Med, 2003, 198(5): 725-736 PMCID: 2194193 PMID: 12939340

[13] ZhangZ, ChoppM, PowersC, et al. . Temporal profile of microglial response following transient (2h) middle cerebral artery occlusion. Brain Res, 1997, 744(2): 189-198 PMID: 9027378

[14] LengletS, MontecuccoF, DenesA, et al. . Recombinant tissue plasminogen activator enhances microglial cell recruitment after stroke in mice. J Cereb Blood Flow Metab, 2014, 34(5): 802-812 PMID: 24473480

[15] KohmanRA, RhodesJS. Neurogenesis, inflammation and behavior. Brain Behav Immun, 2013, 27(1): 22-32 PMID: 22985767

[16] PradillaG, ChaichanaKL, HoangS, et al. . Inflammation and cerebral vasospasm after subarachnoid hemorrhage. Neurosurg Clin N Am, 2010, 21(2): 365-379 PMID: 20380976

[17] YrjanheikkiJ, KeinanenR, PellikkaM, et al. . Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA, 1998, 95(26): 15769-15774 PMCID: 28119 PMID: 9861045

[18] FaganSC, WallerJL, NicholsFT, et al. . Minocycline to improve neurologicoutcome stroke (MINOS): a dose-finding study. Stroke, 2010, 41(10): 2283-2287 PMCID: 3916214 PMID: 20705929

[19] QiuJ, NishimuraM, WangY, et al. . Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab, 2008, 28(5): 927-938 PMID: 18000511

[20] AronowskiJ, ZhaoX. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke, 2011, 42(6): 1781-1786 PMCID: 3123894 PMID: 21527759

[21] LambertsenKL, BiberK, FinsenB. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab, 2012, 32(9): 1677-1698 PMCID: 3434626 PMID: 22739623

[22] PolaR. Inflammatory markers for ischaemic stroke. Thromb Haemost, 2009, 101(5): 800-801 PMID: 19404529

[23] DrabekT, JanataA, WilsonCD, et al. . Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats. Resuscitation, 2014, 85(2): 284-291 PMCID: 3952024 PMID: 24513126

[24] YenariMA. Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci, 2012, 13(4): 267-278 PMID: 22353781

[25] TrendelenburgG. Acute neurodegeneration and the inflammasome: central processor for danger signals and the inflammatory response?. J Cereb Blood Flow Metab, 2008, 28(5): 867-881 PMID: 18212795

[26] DuanY, SahleyCL, MullerKJ. ATP and no dually control migration of microglia to nerve lesions. Dev Neurobiol, 2009, 69(1): 60-72 PMCID: 2748121 PMID: 19025930