Minocycline Attenuates Microglia/Macrophage Phagocytic Activity and Inhibits SAH-Induced Neuronal Cell Death and Inflammation

Overview

Journal Neurocrit Care

Specialty Critical Care

Date 2022 May 18

PMID 35585424

Authors

Kinga G Blecharz-Lang

Victor Patsouris

Melina Nieminen-Kelha

Stefanie Seiffert

Ulf C Schneider

Peter Vajkoczy

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Incidence and Factors in Delayed Neurological Deficits after Subarachnoid Hemorrhage in Mice.

Wroe W, Dienel A, Hong S, Matsumura K, Guzman J, Torres K Brain Hemorrhages. 2025; 5(3):99-106.

PMID: 39830728 PMC: 11741540. DOI: 10.1016/j.hest.2023.12.006.

TLR2/NF-κB signaling in macrophage/microglia mediated COVID-pain induced by SARS-CoV-2 envelope protein.

Cui H, Sun F, Yu N, Cao Y, Wang X, Zhang D iScience. 2024; 27(10):111027.

PMID: 39435149 PMC: 11493200. DOI: 10.1016/j.isci.2024.111027.

Looking Back to Move Forward: Research in Stress, Behavior, and Immune Function.

Kuhn A, Bosis K, Wohleb E Neuroimmunomodulation. 2024; 31(1):211-229.

PMID: 39369707 PMC: 11697378. DOI: 10.1159/000541592.

The pivotal role of microglia in injury and the prognosis of subarachnoid hemorrhage.

Ning W, Lv S, Wang Q, Xu Y Neural Regen Res. 2024; 20(7):1829-1848.

PMID: 38993136 PMC: 11691474. DOI: 10.4103/NRR.NRR-D-24-00241.

Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia.

Luzzi S, Kuru Bektasoglu P, Dogruel Y, Gungor A Neurosurg Rev. 2024; 47(1):305.

PMID: 38967704 PMC: 11226492. DOI: 10.1007/s10143-024-02543-5.

References

Loch Macdonald R, Kassell N, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S . 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. DOI: 10.1161/STROKEAHA.108.519942. View

Loch Macdonald R, Higashida R, Keller E, Mayer S, Molyneux A, Raabe A . 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. DOI: 10.1007/s12028-010-9433-3. View

Alaraj A, Charbel F, Amin-Hanjani S . Peri-operative measures for treatment and prevention of cerebral vasospasm following subarachnoid hemorrhage. Neurol Res. 2009; 31(6):651-9. DOI: 10.1179/174313209X382395. View

Wilkins R, Alexander J, ODOM G . Intracranial arterial spasm: a clinical analysis. J Neurosurg. 1968; 29(2):121-34. DOI: 10.3171/jns.1968.29.2.0121. View

Sehba F, Pluta R, Zhang J . Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol. 2010; 43(1):27-40. PMC: 3023855. DOI: 10.1007/s12035-010-8155-z. View

Hansen-Schwartz J, Vajkoczy P, Macdonald R, Pluta R, Zhang J . Cerebral vasospasm: looking beyond vasoconstriction. Trends Pharmacol Sci. 2007; 28(6):252-6. DOI: 10.1016/j.tips.2007.04.002. View

Pluta R, Hansen-Schwartz J, Dreier J, Vajkoczy P, Loch Macdonald R, Nishizawa S . Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res. 2009; 31(2):151-8. PMC: 2706525. DOI: 10.1179/174313209X393564. View

Schneider U, Davids A, Brandenburg S, Muller A, Elke A, Magrini S . Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol. 2015; 130(2):215-31. DOI: 10.1007/s00401-015-1440-1. View

Heppner F, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N . Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med. 2005; 11(2):146-52. DOI: 10.1038/nm1177. View

10.

Sarrafzadeh A, Copin J, Bengualid D, Turck N, Vajkoczy P, Bijlenga P . 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. DOI: 10.1179/1743132812Y.0000000018. View

11.

Schneider U, 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. PMC: 3305442. DOI: 10.1186/1742-2094-9-28. View

12.

Ishikawa M, Kusaka G, Yamaguchi N, Sekizuka E, Nakadate H, Minamitani H . Platelet and leukocyte adhesion in the microvasculature at the cerebral surface immediately after subarachnoid hemorrhage. Neurosurgery. 2009; 64(3):546-53. DOI: 10.1227/01.NEU.0000337579.05110.F4. View

13.

Atangana E, Schneider U, Blecharz K, Magrini S, Wagner J, Nieminen-Kelha M . Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (eSAH). Transl Stroke Res. 2016; 8(2):144-156. DOI: 10.1007/s12975-016-0485-3. View

14.

Rifkin B, Vernillo A, Golub L, Ramamurthy N . Modulation of bone resorption by tetracyclines. Ann N Y Acad Sci. 1994; 732:165-80. DOI: 10.1111/j.1749-6632.1994.tb24733.x. View

15.

Amin A, Attur M, Thakker G, Patel P, Vyas P, Patel R . A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A. 1996; 93(24):14014-9. PMC: 19486. DOI: 10.1073/pnas.93.24.14014. View

16.

Wang Z, Meng C, Shen X, Shu Z, Ma C, Zhu G . 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. DOI: 10.1007/s12031-012-9769-6. View

17.

Pi R, Li W, Lee N, Chan H, Pu Y, Chan L . Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. J Neurochem. 2004; 91(5):1219-30. DOI: 10.1111/j.1471-4159.2004.02796.x. View

18.

Shultz R, Zhong Y . Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural Regen Res. 2017; 12(5):702-713. PMC: 5461601. DOI: 10.4103/1673-5374.206633. View

19.

Suk K . Minocycline suppresses hypoxic activation of rodent microglia in culture. Neurosci Lett. 2004; 366(2):167-71. DOI: 10.1016/j.neulet.2004.05.038. View

20.

Guo Z, Wu H, Sun X, Zhang X, Zhang J . Protection of minocycline on early brain injury after subarachnoid hemorrhage in rats. Acta Neurochir Suppl. 2010; 110(Pt 1):71-4. DOI: 10.1007/978-3-7091-0353-1_13. View