Neuroprotective effects of minocycline on focal cerebral ischemia injury: a systematic review

Yazdan Naderi, Yunes Panahi, George E Barreto, Amirhosein Sahebkar, Yazdan Naderi, Yunes Panahi, George E Barreto, Amirhosein Sahebkar

Abstract

To review the neuroprotective effects of minocycline in focal cerebral ischemia in animal models. By searching in the databases of PubMed, ScienceDirect, and Scopus, and considering the inclusion and exclusion criteria of the study. Studies were included if focal cerebral ischemia model was performed in mammals and including a control group that has been compared with a minocycline group. Written in languages other than English; duplicate data; in vitro studies and combination of minocycline with other neuroprotective agents were excluded. Neurological function of patients was assessed by National Institute of Health Stroke Scale, modified Rankin Scale, and modified Barthel Index. Neuroprotective effects were assessed by detecting the expression of inflammatory cytokines. We examined 35 papers concerning the protective effects of minocycline in focal cerebral ischemia in animal models and 6 clinical trials which had evaluated the neuroprotective effects of minocycline in ischemic stroke. These studies revealed that minocycline increases the viability of neurons and decreases the infarct volume following cerebral ischemia. The mechanisms that were reported in these studies included anti-inflammatory, antioxidant, as well as anti-apoptotic effects. Minocycline also increases the neuronal regeneration following cerebral ischemia. Minocycline has considerable neuroprotective effects against cerebral ischemia-induced neuronal damages. However, larger clinical trials may be required before using minocycline as a neuroprotective drug in ischemic stroke.

Keywords: ischemic stroke; minocycline; neuronal regeneration; neuroprotection; stroke.

Conflict of interest statement

None

Figures

Figure 1
Figure 1
Minocycline structure.
Figure 2
Figure 2
Flowchart of study selection process.

References

    1. Abbaszadeh A, Darabi S, Hasanvand A, Amini-Khoei H, Abbasnezhad A, Choghakhori R, Aaliehpour A. Minocycline through attenuation of oxidative stress and inflammatory response reduces the neuropathic pain in a rat model of chronic constriction injury. Iran J Basic Med Sci. 2018;21:138–144.
    1. Abraham J, Fox PD, Condello C, Bartolini A, Koh S. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis. 2012;46:425–430.
    1. Amiri-Nikpour MR, Nazarbaghi S, Hamdi-Holasou M, Rezaei Y. An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect. Acta Neurol Scand. 2015;131:45–50.
    1. Aras M, Urfali B, Serarslan Y, Ozgur T, Ulutas KT, Urfali S, Altas M, Yilmaz N. Protective effects of minocycline against short-term ischemia-reperfusion injury in rat brain. Pediatr Neurosurg. 2013;49:172–178.
    1. Broome LJ, Battle CE, Lawrence M, Evans PA, Dennis MS. Cognitive outcomes following thrombolysis in acute ischemic stroke: a systematic review. J Stroke Cerebrovasc Dis. 2016;25:2868–2875.
    1. Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke. 2009;40:e331–339.
    1. Cai Z, Lin S, Fan LW, Pang Y, Rhodes PG. Minocycline alleviates hypoxic-ischemic injury to developing oligodendrocytes in the neonatal rat brain. Neuroscience. 2006;137:425–435.
    1. Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model. Neurosci Bull. 2010;26:28–36.
    1. Cai ZY, Yan Y, Yu CY, Zhang J. Minocycline inhibits neuroinflammation and enhances vascular endothelial growth factor expression in a cerebral ischemia/reperfusion rat model. Neural Regen Res. 2008a;3:1088–1094.
    1. Cai ZY, Yan Y, Sun SQ, Zhang J, Huang LG, Yan N, Wu F, Li JY. Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull. 2008b;24:305–313.
    1. Cardoso MM, Franco EC, de Souza CC, da Silva MC, Gouveia A, Gomes-Leal W. Minocycline treatment and bone marrow mononuclear cell transplantation after endothelin-1 induced striatal ischemia. Inflammation. 2013;36:197–205.
    1. Chen SD, Yin JH, Hwang CS, Tang CM, Yang DI. Anti-apoptotic and anti-oxidative mechanisms of minocycline against sphingomyelinase/ceramide neurotoxicity: implication in Alzheimer’s disease and cerebral ischemia. Free Radic Res. 2012;46:940–950.
    1. Cho BB, Toledo-Pereyra LH. Caspase-independent programmed cell death following ischemic stroke. J Invest Surg. 2008;21:141–147.
    1. Cho KO, La HO, Cho YJ, Sung KW, Kim SY. Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res. 2006;83:285–291.
    1. Chu LS, Fang SH, Zhou Y, Yu GL, Wang ML, Zhang WP, Wei EQ. Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats. Acta Pharmacol Sin. 2007;28:763–772.
    1. Chu LS, Fang SH, Zhou Y, Yin YJ, Chen WY, Li JH, Sun J, Wang ML, Zhang WP, Wei EQ. Minocycline inhibits 5-lipoxygenase expression and accelerates functional recovery in chronic phase of focal cerebral ischemia in rats. Life Sci. 2010;86:170–177.
    1. Corsaro A, Thellung S, Chiovitti K, Villa V, Simi A, Raggi F, Paludi D, Russo C, Aceto A, Florio T. Dual modulation of ERK1/2 and p38 MAP kinase activities induced by minocycline reverses the neurotoxic effects of the prion protein fragment 90-231. Neurotox Res. 2009;15:138–154.
    1. Dai C, Ciccotosto GD, Cappai R, Wang Y, Tang S, Xiao X, Velkov T. Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress. J Antimicrob Chemother. 2017;72:1635–1645.
    1. Defaux A, Zurich MG, Honegger P, Monnet-Tschudi F. Minocycline promotes remyelination in aggregating rat brain cell cultures after interferon-gamma plus lipopolysaccharide-induced demyelination. Neuroscience. 2011;187:84–92.
    1. Dong X, Song YN, Liu WG, Guo XL. Mmp-9, a potential target for cerebral ischemic treatment. Curr Neuropharmacol. 2009;7:269–275.
    1. Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, Hall CE, Switzer JA, Ergul A, Hess DC. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke. 2010;41:2283–2287.
    1. Garwood CJ, Cooper JD, Hanger DP, Noble W. Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Front Psychiatry. 2010;1:136.
    1. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol. 2005;78:135–143.
    1. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Iwasaki K, Fujiwara M. Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke. 2008;39:951–958.
    1. Heo K, Cho YJ, Cho KJ, Kim HW, Kim HJ, Shin HY, Lee BI, Kim GW. Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. Neurosci Lett. 2006;398:195–200.
    1. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21:1359–1369.
    1. Hoda MN, Fagan SC, Khan MB, Vaibhav K, Chaudhary A, Wang P, Dhandapani KM, Waller JL, Hess DC. A 2 x 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model. Exp Transl Stroke Med. 2014;6:10.
    1. Hoda MN, Li W, Ahmad A, Ogbi S, Zemskova MA, Johnson MH, Ergul A, Hill WD, Hess DC, Sazonova IY. Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med. 2011;3:16.
    1. Jianrong S, Yanjun Z, Chen Y, Jianwen X. DUSP14 rescues cerebral ischemia/reperfusion (IR) injury by reducing inflammation and apoptosis via the activation of Nrf-2. Biochem Biophys Res Commun. 2019;509:713–721.
    1. Jin K, Graham SH, Mao X, Nagayama T, Simon RP, Greenberg DA. Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:1411–1421.
    1. Jin Z, Liang J, Wang J, Kolattukudy PE. MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia/reperfusion injury in vitro and in vivo. J Neuroinflammation. 2015;12:39.
    1. Kawabori M, Yenari MA. Inflammatory responses in brain ischemia. Curr Med Chem. 2015;22:1258–1277.
    1. Kelly KJ, Sutton TA, Weathered N, Ray N, Caldwell EJ, Plotkin Z, Dagher PC. Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. Am J Physiol Renal Physiol. 2004;287:F760–766.
    1. Kim BJ, Kim MJ, Park JM, Lee SH, Kim YJ, Ryu S, Kim YH, Yoon BW. Reduced neurogenesis after suppressed inflammation by minocycline in transient cerebral ischemia in rat. J Neurol Sci. 2009;279:70–75.
    1. Klöfers M, Kohaut J, Bendix I, Herz J, Boos V, Felderhoff-Müser U, Dzietko M. Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury. Biomed Res Int. 2017;2017:2924848.
    1. Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, Blacker D. Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke. 2013;44:2493–2499.
    1. Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, Opdenakker G, Koistinaho J. Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab. 2005;25:460–467.
    1. Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol. 2014;115:157–188.
    1. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab. 2012;32:1677–1698.
    1. Li W, Yang S. Targeting oxidative stress for the treatment of ischemic stroke: Upstream and downstream therapeutic strategies. Brain Circ. 2016;2:153–163.
    1. Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007;38:146–152.
    1. Lu Y, Xiao G, Luo W. Minocycline suppresses NLRP3 inflammasome activation in experimental ischemic stroke. Neuroimmunomodulation. 2016;23:230–238.
    1. 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.
    1. Martín A, Boisgard R, Kassiou M, Dollé F, Tavitian B. Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a PET study using [(18)F]DPA-714. Mol Imaging Biol. 2011;13:10–15.
    1. Matsukawa N, Yasuhara T, Hara K, Xu L, Maki M, Yu G, Kaneko Y, Ojika K, Hess DC, Borlongan CV. Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke. BMC Neurosci. 2009;10:126.
    1. Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res. 2005;1044:8–15.
    1. Moussaddy A, Demchuk AM, Hill MD. Thrombolytic therapies for ischemic stroke: Triumphs and future challenges. Neuropharmacology. 2018;134:272–279.
    1. Muralikrishna Adibhatla R, Hatcher JF. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med. 2006;40:376–387.
    1. Naderi Y, Sabetkasaei M, Parvardeh S, Moini Zanjani T. Neuroprotective effects of pretreatment with minocycline on memory impairment following cerebral ischemia in rats. Behav Pharmacol. 2017a;28:214–222.
    1. Naderi Y, Sabetkasaei M, Parvardeh S, Zanjani TM. Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat. Brain Res Bull. 2017b;131:207–213.
    1. Niizuma K, Endo H, Nito C, Myer DJ, Chan PH. Potential role of PUMA in delayed death of hippocampal CA1 neurons after transient global cerebral ischemia. Stroke. 2009;40:618–625.
    1. Niizuma K, Yoshioka H, Chen H, Kim GS, Jung JE, Katsu M, Okami N, Chan PH. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta. 2010;1802:92–99.
    1. Nikodemova M, Duncan ID, Watters JJ. Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem. 2006;96:314–323.
    1. Nita DA, Nita V, Spulber S, Moldovan M, Popa DP, Zagrean AM, Zagrean L. Oxidative damage following cerebral ischemia depends on reperfusion - a biochemical study in rat. J Cell Mol Med. 2001;5:163–170.
    1. Ortega-Arellano HF, Jimenez-Del-Rio M, Velez-Pardo C. Minocycline protects, rescues and prevents knockdown transgenic parkin Drosophila against paraquat/iron toxicity: Implications for autosomic recessive juvenile parkinsonism. Neurotoxicology. 2017;60:42–53.
    1. Padma Srivastava MV, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, Singh MB, Tripathi M. Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial. Neurol India. 2012;60:23–28.
    1. 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.
    1. Park CH, Shin TK, Lee HY, Kim SJ, Lee WS. Matrix metalloproteinase inhibitors attenuate neuroinflammation following focal cerebral ischemia in mice. Korean J Physiol Pharmacol. 2011;15:115–122.
    1. Park SI, Park SK, Jang KS, Han YM, Kim CH, Oh SJ. Preischemic neuroprotective effect of minocycline and sodium ozagrel on transient cerebral ischemic rat model. Brain Res. 2015;1599:85–92.
    1. Piccardi B, Arba F, Nesi M, Palumbo V, Nencini P, Giusti B, Sereni A, Gadda D, Moretti M, Fainardi E, Mangiafico S, Pracucci G, Nannoni S, Galmozzi F, Fanelli A, Pezzati P, Vanni S, Grifoni S, Sarti C, Lamassa M, et al. Reperfusion Injury after ischemic Stroke Study (RISKS): single-centre (Florence, Italy), prospective observational protocol study. BMJ Open. 2018;8:e021183.
    1. Radak D, Katsiki N, Resanovic I, Jovanovic A, Sudar-Milovanovic E, Zafirovic S, Mousad SA, Isenovic ER. Apoptosis and acute brain ischemia in ischemic stroke. Curr Vasc Pharmacol. 2017;15:115–122.
    1. Sancho M, Herrera AE, Gortat A, Carbajo RJ, Pineda-Lucena A, Orzáez M, Pérez-Payá E. Minocycline inhibits cell death and decreases mutant Huntingtin aggregation by targeting Apaf-1. Hum Mol Genet. 2011;20:3545–3553.
    1. Shirley R, Ord EN, Work LM. Oxidative stress and the use of antioxidants in stroke. Antioxidants (Basel) 2014;3:472–501.
    1. Soliman S, Ishrat T, Fouda AY, Patel A, Pillai B, Fagan SC. Sequential therapy with minocycline and candesartan improves long-term recovery after experimental stroke. Transl Stroke Res. 2015;6:309–322.
    1. Sonmez E, Kabatas S, Ozen O, Karabay G, Turkoglu S, Ogus E, Yilmaz C, Caner H, Altinors N. Minocycline treatment inhibits lipid peroxidation, preserves spinal cord ultrastructure, and improves functional outcome after traumatic spinal cord injury in the rat. Spine (Phila Pa 1976) 2013;38:1253–1259.
    1. Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN, Yang Y. Free radical damage in ischemia-reperfusion injury: an obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev. 2018;2018:3804979.
    1. Switzer JA, Sikora A, Ergul A, Waller JL, Hess DC, Fagan SC. Minocycline prevents IL-6 increase after acute ischemic stroke. Transl Stroke Res. 2012;3:363–368.
    1. Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM, Fagan SC. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42:2633–2635.
    1. Szeto GL, Pomerantz JL, Graham DR, Clements JE. Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J Biol Chem. 2011;286:11275–11282.
    1. Tanaka M, Ishihara Y, Mizuno S, Ishida A, Vogel CF, Tsuji M, Yamazaki T, Itoh K. Progression of vasogenic edema induced by activated microglia under permanent middle cerebral artery occlusion. Biochem Biophys Res Commun. 2018;496:582–587.
    1. Tang XN, Wang Q, Koike MA, Cheng D, Goris ML, Blankenberg FG, Yenari MA. Monitoring the protective effects of minocycline treatment with radiolabeled annexin V in an experimental model of focal cerebral ischemia. J Nucl Med. 2007;48:1822–1828.
    1. Tao T, Xu G, Si Chen C, Feng J, Kong Y, Qin X. Minocycline promotes axonal regeneration through suppression of RGMa in rat MCAO/reperfusion model. Synapse. 2013;67:189–198.
    1. Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol. 2013;2013:746068.
    1. Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166:7527–7533.
    1. Vidale S, Consoli A, Arnaboldi M, Consoli D. Postischemic Inflammation in Acute Stroke. J Clin Neurol. 2017;13:1–9.
    1. Wang J, Wei Q, Wang CY, Hill WD, Hess DC, Dong Z. Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem. 2004;279:19948–19954.
    1. Weinstein JR, Koerner IP, Möller T. Microglia in ischemic brain injury. Future Neurol. 2010;5:227–246.
    1. Wu Y, Chen Y, Wu Q, Jia L, Du X. Minocycline inhibits PARP1 expression and decreases apoptosis in diabetic retinopathy. Mol Med Rep. 2015;12:4887–4894.
    1. Xu L, Fagan SC, Waller JL, Edwards D, Borlongan CV, Zheng J, Hill WD, Feuerstein G, Hess DC. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol. 2004;4:7.
    1. Yang Y, Salayandia VM, Thompson JF, Yang LY, Estrada EY, Yang Y. Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery. J Neuroinflammation. 2015;12:26.
    1. Yew WP, Djukic ND, Jayaseelan JSP, Walker FR, Roos KAA, Chataway TK, Muyderman H, Sims NR. Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. J Neuroinflammation. 2019;16:6.
    1. Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. 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;96:13496–13500.
    1. Zhao Y, Xiao M, He W, Cai Z. Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits. Neuropsychiatr Dis Treat. 2015;11:507–516.
    1. Zheng Y, Xu L, Yin J, Zhong Z, Fan H, Li X, Chang Q. Effect of minocycline on cerebral ischemia-reperfusion injury. Neural Regen Res. 2013;8:900–908.

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