Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Attenuation of acute stroke injury in rat brain by minocycline promotes blood–brain barrier remodeling and alternative microglia/macrophage activation during recovery

Authors: Yirong Yang, Victor M Salayandia, Jeffrey F Thompson, Lisa Y Yang, Eduardo Y Estrada, Yi Yang

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

Abstract

Background

Minocycline reduces reperfusion injury by inhibiting matrix metalloproteinases (MMPs) and microglia activity after cerebral ischemia. Prior studies of minocycline investigated short-term neuroprotective effects during subacute stage of stroke; however, the late effects of minocycline against early reperfusion injury on neurovascular remodeling are less well studied. We have shown that spontaneous angiogenesis vessels in ischemic brain regions have high blood–brain barrier (BBB) permeability due to lack of major tight junction proteins (TJPs) in endothelial cells at three weeks. In the present study, we longitudinally investigated neurological outcome, neurovascular remodeling and microglia/macrophage alternative activation after spontaneous and minocycline-induced stroke recovery.

Methods

Adult spontaneously hypertensive rats had a 90 minute transient middle cerebral artery occlusion. At the onset of reperfusion they received a single dose of minocycline (3 mg/kg intravenously) or a vehicle. They were studied at multiple time points up to four weeks with magnetic resonance imaging (MRI), immunohistochemistry and biochemistry.

Results

Minocycline significantly reduced the infarct size and prevented tissue loss in the ischemic hemispheres compared to vehicle-treated rats from two to four weeks as measured with MRI. Cerebral blood flow measured with arterial spin labeling (ASL) showed that minocycline improved perfusion. Dynamic contrast-enhanced MRI indicated that minocycline reduced BBB permeability accompanied with higher levels of TJPs measured with Western blot. Increased MMP-2 and −3 were detected at four weeks. Active microglia/macrophage, surrounding and within the peri-infarct areas, expressed YM1, a marker of M2 microglia/macrophage activation, at four weeks. These microglia/macrophage expressed both pro-inflammatory factors tumor necrosis factors-α (TNF-α) and interleukin-1β (IL-1β) and anti-inflammatory factors transforming growth factor-β (TGF-β) and interleukin-10 (IL-10). Treatment with minocycline significantly reduced levels of TNF-α and IL-1β, and increased levels of TGF-β, IL-10 and YM1.

Conclusions

Early minocycline treatment against reperfusion injury significantly promotes neurovascular remodeling during stroke recovery by reducing brain tissue loss, enhancing TJP expression in ischemic brains and facilitating neuroprotective phenotype alternative activation of microglia/macrophages.
Appendix
Available only for authorised users
Literature
1.
Yang Y, Candelario-Jalil E, Thompson JF, Cuadrado E, Estrada EY, Rosell A, et al. Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia. J Neurochem. 2010;112:134–49.CrossRefPubMed
2.
Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27:697–709.CrossRefPubMed
3.
Yang Y, Thompson JF, Taheri S, Salayandia VM, McAvoy TA, Hill JW, et al. Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery. J Cereb Blood Flow Metab. 2013;33:1104–14.CrossRefPubMedCentralPubMed
4.
5.
Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008;39:3372–7.CrossRefPubMedCentralPubMed
6.
Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, et al. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke. 2010;41:2283–7.CrossRefPubMedCentralPubMed
7.
Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, et al. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42:2633–5.CrossRefPubMedCentralPubMed
8.
Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7:56.CrossRefPubMedCentralPubMed
9.
Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, et al. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke. 2009;40:3028–33.CrossRefPubMedCentralPubMed
10.
Lee CZ, Yao JS, Huang Y, Zhai W, Liu W, Guglielmo BJ, et al. Dose–response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation. J Cereb Blood Flow Metab. 2006;26:1157–64.PubMed
11.
Jin X, Liu J, Liu KJ, Rosenberg GA, Yang Y, Liu W. Normobaric hyperoxia combined with minocycline provides greater neuroprotection than either alone in transient focal cerebral ischemia. Exp Neurol. 2013;240:9–16.CrossRefPubMedCentralPubMed
12.
Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiate damage to blood–brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke. 2006;37:1087–93.CrossRefPubMed
13.
14.
Emsley HC, Tyrrell PJ. Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab. 2002;22:1399–419.CrossRefPubMed
15.
16.
Oliveira GB, Fontes Ede Jr A, de Carvalho S, da Silva JB, Fernandes LM, Oliveira MC, et al. Minocycline mitigates motor impairments and cortical neuronal loss induced by focal ischemia in rats chronically exposed to ethanol during adolescence. Brain Res. 2014;1561:23–34.CrossRefPubMed
17.
Lartey FM, Ahn GO, Ali R, Rosenblum S, Miao Z, Arksey N, et al. The relationship between serial [(18) F]PBR06 PET imaging of microglial activation and motor function following stroke in mice. Mol Imaging Biol. 2014;16:81–9.
18.
Lampron A, Elali A, Rivest S. Innate immunity in the CNS: redefining the relationship between the CNS and its environment. Neuron. 2013;78:214–32.CrossRefPubMed
19.
Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.CrossRefPubMed
20.
21.
Giunti D, Parodi B, Cordano C, Uccelli A, Kerlero de Rosbo N. Can we switch microglia’s phenotype to foster neuroprotection? Focus on multiple sclerosis. Immunology. 2014;141:328–39.CrossRefPubMed
22.
Cramer SC. Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann Neurol. 2008;63:272–87.CrossRefPubMed
23.
Cramer SC. Repairing the human brain after stroke: II. Restorative therapies. Ann Neurol. 2008;63:549–60.CrossRefPubMed
24.
Yang Y, Hill JW, Rosenberg GA. Multiple roles of metalloproteinases in neurological disorders. Prog Mol Biol Transl Sci. 2011;99:241–63.CrossRefPubMed
25.
Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, et al. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol. 2004;4:7.CrossRefPubMedCentralPubMed
26.
Hill JW, Poddar R, Thompson JF, Rosenberg GA, Yang Y. Intranuclear matrix metalloproteinases promote DNA damage and apoptosis induced by oxygen-glucose deprivation in neurons. Neuroscience. 2012;220:277–90.CrossRefPubMed
27.
Sood R, Yang Y, Taheri S, Candelario-Jalil E, Estrada EY, Walker EJ, et al. Increased apparent diffusion coefficients on MRI linked with matrix metalloproteinases and edema in white matter after bilateral carotid artery occlusion in rats. J Cereb Blood Flow Metab. 2009;29:308–16.CrossRefPubMed
28.
Taheri S, Sood R. Partial volume effect compensation for improved reliability of quantitative blood–brain barrier permeability. Magn Reson Imaging. 2007;25:613–25.CrossRefPubMed
29.
Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3:1–7.CrossRefPubMed
30.
Ewing JR, Knight RA, Nagaraja TN, Yee JS, Nagesh V, Whitton PA, et al. Patlak plots of Gd-DTPA MRI data yield blood–brain transfer constants concordant with those of 14C-sucrose in areas of blood–brain opening. Magn Reson Med. 2003;50:283–92.CrossRefPubMed
31.
Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke. 2001;32:1208–15.CrossRefPubMed
32.
Patel AR, Ritzel R, McCullough LD, Liu F. Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol. 2013;5:73–90.PubMedCentralPubMed
33.
Li Q, Lau A, Morris TJ, Guo L, Fordyce CB, Stanley EF. A syntaxin 1, Galpha(o), and N-type calcium channel complex at a presynaptic nerve terminal: analysis by quantitative immunocolocalization. J Neurosci. 2004;24:4070–81.CrossRefPubMed
34.
Charlton RA, Barrick TR, McIntyre DJ, Shen Y, O’Sullivan M, Howe FA, et al. White matter damage on diffusion tensor imaging correlates with age-related cognitive decline. Neurology. 2006;66:217–22.CrossRefPubMed
35.
Tanaka Y, Nagaoka T, Nair G, Ohno K, Duong TQ. Arterial spin labeling and dynamic susceptibility contrast CBF MRI in postischemic hyperperfusion, hypercapnia, and after mannitol injection. J Cereb Blood Flow Metab. 2011;31:1403–11.CrossRefPubMedCentralPubMed
36.
37.
Schilling M, Besselmann M, Muller M, Strecker JK, Ringelstein EB, Kiefer R. Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol. 2005;196:290–7.CrossRefPubMed
38.
Snook ER, Fisher-Perkins JM, Sansing HA, Lee KM, Alvarez X, MacLean AG, et al. Innate immune activation in the pathogenesis of a murine model of globoid cell leukodystrophy. Am J Pathol. 2014;184:382–96.CrossRefPubMedCentralPubMed
39.
McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci. 2008;28:9451–62.CrossRefPubMed
40.
Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke. 2008;39:1121–6.CrossRefPubMed
41.
Schaller B, Graf R. Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab. 2004;24:351–71.CrossRefPubMed
42.
Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J. Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology. 2007;49:93–102.CrossRefPubMedCentralPubMed
43.
44.
Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007;38:146–52.CrossRefPubMed
45.
Weng YC, Kriz J. Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Exp Neurol. 2007;204:433–42.CrossRefPubMed
46.
Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 2013;4:e525.CrossRefPubMedCentralPubMed
47.
Hewlett KA, Corbett D. Delayed minocycline treatment reduces long-term functional deficits and histological injury in a rodent model of focal ischemia. Neuroscience. 2006;141:27–33.CrossRefPubMed
48.
Ozen I, Deierborg T, Miharada K, Padel T, Englund E, Genove G, et al. Brain pericytes acquire a microglial phenotype after stroke. Acta Neuropathol. 2014;128:381–96.CrossRefPubMedCentralPubMed
49.
Ronaldson PT, Demarco KM, Sanchez-Covarrubias L, Solinsky CM, Davis TP. Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood–brain barrier during inflammatory pain. J Cereb Blood Flow Metab. 2009;29:1084–98.CrossRefPubMedCentralPubMed
50.
Dohgu S, Yamauchi A, Takata F, Naito M, Tsuruo T, Higuchi S, et al. Transforming growth factor-beta1 upregulates the tight junction and P-glycoprotein of brain microvascular endothelial cells. Cell Mol Neurobiol. 2004;24:491–7.CrossRefPubMed
Metadata
Title
Attenuation of acute stroke injury in rat brain by minocycline promotes blood–brain barrier remodeling and alternative microglia/macrophage activation during recovery
Authors
Yirong Yang
Victor M Salayandia
Jeffrey F Thompson
Lisa Y Yang
Eduardo Y Estrada
Yi Yang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0245-4

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue

Research

Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone IIA sulfonate in neuropathic pain

Research

The induction of neuronal death by up-regulated microglial cathepsin H in LPS-induced neuroinflammation

Research

Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury

Research

Inhibition of NADPH oxidase activation reduces EAE-induced white matter damage in mice

Research

Lipopolysaccharide binding protein, interleukin-10, interleukin-6 and C-reactive protein blood levels in acute ischemic stroke patients with post-stroke infection

Research

PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene