Minocycline Attenuates Microglia/Macrophage Phagocytic Activity and Inhibits SAH-Induced Neuronal Cell Death and Inflammation.
Animals
Anti-Inflammatory Agents
/ pharmacology
Apoptosis
Brain Injuries
/ complications
Cell Death
Cytokines
/ metabolism
Inflammation
/ drug therapy
Macrophages
Mice
Microglia
/ metabolism
Minocycline
/ pharmacology
Neuroprotective Agents
/ pharmacology
Rats
Rats, Sprague-Dawley
Subarachnoid Hemorrhage
/ complications
Anti-inflammatory agents
Apoptosis
Cytokines
Inflammation
Microglia
Phagocytosis
Subarachnoid hemorrhage
Journal
Neurocritical care
ISSN: 1556-0961
Titre abrégé: Neurocrit Care
Pays: United States
ID NLM: 101156086
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
12
08
2021
accepted:
05
04
2022
pubmed:
19
5
2022
medline:
1
10
2022
entrez:
18
5
2022
Statut:
ppublish
Résumé
Neuroprotective treatment strategies aiming at interfering with either inflammation or cell death indicate the importance of these mechanisms in the development of brain injury after subarachnoid hemorrhage (SAH). This study was undertaken to evaluate the influence of minocycline on microglia/macrophage cell activity and its neuroprotective and anti-inflammatory impact 14 days after aneurismal SAH in mice. Endovascular filament perforation was used to induce SAH in mice. SAH + vehicle-operated mice were used as controls for SAH vehicle-treated mice and SAH + minocycline-treated mice. The drug administration started 4 h after SAH induction and was daily repeated until day 7 post SAH and continued until day 14 every second day. Brain cryosections were immunolabeled for Iba1 to detect microglia/macrophages and NeuN to visualize neurons. Phagocytosis assay was performed to determine the microglia/macrophage activity status. Apoptotic cells were stained using terminal deoxyuridine triphosphate nick end labeling. Real-time quantitative polymerase chain reaction was used to estimate cytokine gene expression. We observed a significantly reduced phagocytic activity of microglia/macrophages accompanied by a lowered spatial interaction with neurons and reduced neuronal apoptosis achieved by minocycline administration after SAH. Moreover, the SAH-induced overexpression of pro-inflammatory cytokines and neuronal cell death was markedly attenuated by the compound. Minocycline treatment may be implicated as a therapeutic approach with long-term benefits in the management of secondary brain injury after SAH in a clinically relevant time window.
Sections du résumé
BACKGROUND
Neuroprotective treatment strategies aiming at interfering with either inflammation or cell death indicate the importance of these mechanisms in the development of brain injury after subarachnoid hemorrhage (SAH). This study was undertaken to evaluate the influence of minocycline on microglia/macrophage cell activity and its neuroprotective and anti-inflammatory impact 14 days after aneurismal SAH in mice.
METHODS
Endovascular filament perforation was used to induce SAH in mice. SAH + vehicle-operated mice were used as controls for SAH vehicle-treated mice and SAH + minocycline-treated mice. The drug administration started 4 h after SAH induction and was daily repeated until day 7 post SAH and continued until day 14 every second day. Brain cryosections were immunolabeled for Iba1 to detect microglia/macrophages and NeuN to visualize neurons. Phagocytosis assay was performed to determine the microglia/macrophage activity status. Apoptotic cells were stained using terminal deoxyuridine triphosphate nick end labeling. Real-time quantitative polymerase chain reaction was used to estimate cytokine gene expression.
RESULTS
We observed a significantly reduced phagocytic activity of microglia/macrophages accompanied by a lowered spatial interaction with neurons and reduced neuronal apoptosis achieved by minocycline administration after SAH. Moreover, the SAH-induced overexpression of pro-inflammatory cytokines and neuronal cell death was markedly attenuated by the compound.
CONCLUSIONS
Minocycline treatment may be implicated as a therapeutic approach with long-term benefits in the management of secondary brain injury after SAH in a clinically relevant time window.
Identifiants
pubmed: 35585424
doi: 10.1007/s12028-022-01511-5
pii: 10.1007/s12028-022-01511-5
pmc: PMC9519684
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Cytokines
0
Neuroprotective Agents
0
Minocycline
FYY3R43WGO
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
410-423Informations de copyright
© 2022. The Author(s).
Références
Macdonald RL, Kassell NF, Mayer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39(11):3015–21.
pubmed: 18688013
doi: 10.1161/STROKEAHA.108.519942
Macdonald RL, Higashida RT, Keller E, et al. Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care. 2010;13(3):416–24.
pubmed: 20838933
doi: 10.1007/s12028-010-9433-3
Alaraj A, Charbel FT, Amin-Hanjani S. Peri-operative measures for treatment and prevention of cerebral vasospasm following subarachnoid hemorrhage. Neurol Res. 2009;31(6):651–9.
pubmed: 19133166
doi: 10.1179/174313209X382395
Wilkins RH, Alexander JA, Odom GL. Intracranial arterial spasm: a clinical analysis. J Neurosurg. 1968;29(2):121–34.
pubmed: 5673310
doi: 10.3171/jns.1968.29.2.0121
Sehba FA, Pluta RM, Zhang JH. Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol. 2011;43(1):27–40.
pubmed: 21161614
doi: 10.1007/s12035-010-8155-z
Hansen-Schwartz J, Vajkoczy P, Macdonald RL, Pluta RM, Zhang JH. Cerebral vasospasm: looking beyond vasoconstriction. Trends Pharmacol Sci. 2007;28(6):252–6.
pubmed: 17466386
doi: 10.1016/j.tips.2007.04.002
Pluta RM, Hansen-Schwartz J, Dreier J, et al. Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res. 2009;31(2):151–8.
pubmed: 19298755
pmcid: 2706525
doi: 10.1179/174313209X393564
Schneider UC, Davids AM, Brandenburg S, et al. Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol. 2015;130(2):215–31.
pubmed: 25956409
doi: 10.1007/s00401-015-1440-1
Heppner FL, Greter M, Marino D, et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med. 2005;11(2):146–52.
pubmed: 15665833
doi: 10.1038/nm1177
Sarrafzadeh A, Copin JC, Bengualid DJ, et al. Matrix metalloproteinase-9 concentration in the cerebral extracellular fluid of patients during the acute phase of aneurysmal subarachnoid hemorrhage. Neurol Res. 2012;34(5):455–61.
pubmed: 22449315
doi: 10.1179/1743132812Y.0000000018
Fassbender K, Hodapp B, Rossol S, et al. Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psych. 2001;70(4):534–7.
doi: 10.1136/jnnp.70.4.534
Schneider UC, Schiffler J, Hakiy N, Horn P, Vajkoczy P. Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro. J Neuroinflammation. 2012;9:28.
pubmed: 22316109
pmcid: 3305442
doi: 10.1186/1742-2094-9-28
Ishikawa M, Kusaka G, Yamaguchi N, et al. Platelet and leukocyte adhesion in the microvasculature at the cerebral surface immediately after subarachnoid hemorrhage. Neurosurgery. 2009;64(3):546–53 (discussion 53-4).
pubmed: 19240618
doi: 10.1227/01.NEU.0000337579.05110.F4
Atangana E, Schneider UC, Blecharz K, et al. Intravascular inflammation triggers intracerebral activated microglia and contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Transl Stroke Res. 2017;8(2):144–56.
pubmed: 27477569
doi: 10.1007/s12975-016-0485-3
Rifkin BR, Vernillo AT, Golub LM, Ramamurthy NS. Modulation of bone resorption by tetracyclines. Ann N Y Acad Sci. 1994;732:165–80.
pubmed: 7978789
doi: 10.1111/j.1749-6632.1994.tb24733.x
Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A. 1996;93(24):14014–9.
pubmed: 8943052
pmcid: 19486
doi: 10.1073/pnas.93.24.14014
Wang Z, Meng CJ, Shen XM, et al. Potential contribution of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 to blood-brain barrier disruption and brain edema after experimental subarachnoid hemorrhage. J Mol Neurosci. 2012;48(1):273–80.
pubmed: 22528459
doi: 10.1007/s12031-012-9769-6
Pi R, Li W, Lee NT, et al. Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. J Neurochem. 2004;91(5):1219–30.
pubmed: 15569265
doi: 10.1111/j.1471-4159.2004.02796.x
Shultz RB, Zhong Y. Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural Regen Res. 2017;12(5):702–13.
pubmed: 28616020
pmcid: 5461601
doi: 10.4103/1673-5374.206633
Suk K. Minocycline suppresses hypoxic activation of rodent microglia in culture. Neurosci Lett. 2004;366(2):167–71.
pubmed: 15276240
doi: 10.1016/j.neulet.2004.05.038
Guo ZD, Wu HT, Sun XC, Zhang XD, Zhang JH. Protection of minocycline on early brain injury after subarachnoid hemorrhage in rats. Acta Neurochir Suppl. 2011;110(Pt 1):71–4.
pubmed: 21116918
Sherchan P, Lekic T, Suzuki H, et al. Minocycline improves functional outcomes, memory deficits, and histopathology after endovascular perforation-induced subarachnoid hemorrhage in rats. J Neurotrauma. 2011;28(12):2503–12.
pubmed: 22013966
pmcid: 3235340
doi: 10.1089/neu.2011.1864
Li J, Chen J, Mo H, et al. Minocycline protects against NLRP3 inflammasome-induced inflammation and P53-associated apoptosis in early brain injury after subarachnoid hemorrhage. Mol Neurobiol. 2016;53(4):2668–78.
pubmed: 26143258
doi: 10.1007/s12035-015-9318-8
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19(8):312–8.
pubmed: 8843599
doi: 10.1016/0166-2236(96)10049-7
McGeer EG, McGeer PL. Brain inflammation in Alzheimer disease and the therapeutic implications. Curr Pharm Des. 1999;5(10):821–36.
pubmed: 10526088
Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol. 1995;38(3):357–66.
pubmed: 7668820
doi: 10.1002/ana.410380304
Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10(11):1387–94.
pubmed: 17965659
doi: 10.1038/nn1997
Szalay G, Martinecz B, Lénárt N, et al. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun. 2016;7:11499.
pubmed: 27139776
pmcid: 4857403
doi: 10.1038/ncomms11499
van Rossum D, Hanisch UK. Microglia. Metab Brain Dis. 2004;19(3–4):393–411.
pubmed: 15554430
doi: 10.1023/B:MEBR.0000043984.73063.d8
de Beer MC, Zhao Z, Webb NR, van der Westhuyzen DR, de Villiers WJ. Lack of a direct role for macrosialin in oxidized LDL metabolism. J Lipid Res. 2003;44(4):674–85.
pubmed: 12562841
doi: 10.1194/jlr.M200444-JLR200
Huang CY, Chen YL, Li AH, Lu JC, Wang HL. Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons. J Neuroinflammation. 2014;11:7.
pubmed: 24405660
pmcid: 3896825
doi: 10.1186/1742-2094-11-7
Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci. 2007;27(9):2357–68.
pubmed: 17329433
pmcid: 6673468
doi: 10.1523/JNEUROSCI.0138-07.2007
Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005;115(1–2):71–83.
pubmed: 15836971
doi: 10.1016/j.pain.2005.02.009
Yrjänheikki J, Tikka T, Keinänen R, et al. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96(23):13496–500.
pubmed: 10557349
pmcid: 23976
doi: 10.1073/pnas.96.23.13496
Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17(7):796–808.
pubmed: 21738161
pmcid: 3137275
doi: 10.1038/nm.2399
Patel RN, Attur MG, Dave MN, et al. A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production. J Immunol. 1999;163(6):3459–67.
pubmed: 10477618
Gong K, Zou X, Fuchs PN, Lin Q. Minocycline inhibits neurogenic inflammation by blocking the effects of tumor necrosis factor-α. Clin Exp Pharmacol Physiol. 2015;42:940–9.
pubmed: 26175075
doi: 10.1111/1440-1681.12444
Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96(Pt A):70–82.
pubmed: 25445483
doi: 10.1016/j.neuropharm.2014.10.027
Pugazhenthi S, Zhang Y, Bouchard R, Mahaffey G. Induction of an inflammatory loop by interleukin-1β and tumor necrosis factor-α involves NF-kB and STAT-1 in differentiated human neuroprogenitor cells. PLoS ONE. 2013;8(7): e69585.
pubmed: 23922745
pmcid: 3726669
doi: 10.1371/journal.pone.0069585
Snow WM, Stoesz BM, Kelly DM, Albensi BC. Roles for NF-κB and gene targets of NF-κB in synaptic plasticity, memory, and navigation. Mol Neurobiol. 2014;49(2):757–70.
pubmed: 24122352
doi: 10.1007/s12035-013-8555-y
Liaury K, Miyaoka T, Tsumori T, et al. Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model. J Neuroinflammation. 2012;9:56.
pubmed: 22424389
pmcid: 3334707
doi: 10.1186/1742-2094-9-56
Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21(8):2580–8.
pubmed: 11306611
pmcid: 6762519
doi: 10.1523/JNEUROSCI.21-08-02580.2001
Gomes JA, Selim M, Cotleur A, et al. Brain iron metabolism and brain injury following subarachnoid hemorrhage: iCeFISH-pilot (CSF iron in SAH). Neurocrit Care. 2014;21(2):285–93.
pubmed: 24710655
pmcid: 4628549
doi: 10.1007/s12028-014-9977-8
Vellimana AK, Zhou ML, Singh I, et al. Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase-9 inhibition. Ann Clin Transl Neurol. 2017;4(12):865–76.
pubmed: 29296615
pmcid: 5740245
doi: 10.1002/acn3.492
Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009;29(4):670–4.
pubmed: 19190654
doi: 10.1038/jcbfm.2009.3