Delayed minocycline but not delayed mild hypothermia protects against embolic stroke

Wang, Chen Xu; Yang, Tao; Noor, Raza; Shuaib, Ashfaq

doi:10.1186/1471-2377-2-2

Cited by 54 publications

(39 citation statements)

References 21 publications

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“…It has very good blood-brain barrier penetration, has rapid absorption and adequate tissue levels within hours after oral or parenteral administration, and has a low side-effect profile making it an attractive agent for clinical use. Minocycline has been shown to have neuroprotective effects by attenuating microglial activation in adult global and focal ischemia models (Wang et al, 2002;Yenari et al, 2006;Yrjanheikki et al, 1998Yrjanheikki et al, , 1999. A recent clinical trial indicated a protective effect of minocycline in acute stroke (Lampl et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…For example, RANTES is primarily regulated and secreted by T cells, which can cross the blood-brain barrier after cerebral ischemia (Terao et al, 2008). Minocycline has been used to ameliorate microglial activation (Jantzie et al, 2005;Wang et al, 2002;Yrjanheikki et al, 1998). It has very good blood-brain barrier penetration, has rapid absorption and adequate tissue levels within hours after oral or parenteral administration, and has a low side-effect profile making it an attractive agent for clinical use.…”

Section: Discussionmentioning

confidence: 99%

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Minocycline Reduces Neuronal Death and Attenuates Microglial Response after Pediatric Asphyxial Cardiac Arrest

Tang

Alexander

Clark

et al. 2009

J Cereb Blood Flow Metab

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The mechanisms leading to delayed neuronal death after asphyxial cardiac arrest (ACA) in the developing brain are unknown. This study aimed at investigating the possible role of microglial activation in neuronal death in developing brain after ACA. Postnatal day-17 rats were subjected to 9 mins of ACA followed by resuscitation. Rats were randomized to treatment with minocycline, (90 mg/kg, intraperitoneally (i.p.)) or vehicle (saline, i.p.) at 1 h after return of spontaneous circulation. Thereafter, minocycline (22.5 mg/kg, i.p.) was administrated every 12 h until sacrifice. Microglial activation (evaluated by immunohistochemistry using ionized calcium-binding adapter molecule-1 (Iba1) antibody) coincided with DNA fragmentation and neurodegeneration in CA1 hippocampus and cortex (assessed by deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL), Fluoro-Jade-B and Nissl stain). Minocycline significantly decreased both the microglial response and neuronal degeneration compared with the vehicle. Asphyxial CA significantly enhanced proinflammatory cytokine and chemokine levels in hippocampus versus control (assessed by multiplex bead array assay), specifically tumor necrosis factor-a (TNF-a), macrophage inflammatory protein-1a (MIP-1a), regulated upon activation, normal T-cell expressed and secreted (RANTES), and growth-related oncogene (GRO-KC) (P < 0.05). Minocycline attenuated ACA-induced increases in MIP-1a and RANTES (P < 0.05). These data show that microglial activation and cytokine production are increased in immature brain after ACA. The beneficial effect of minocycline suggests an important role for microglia in selective neuronal death after pediatric ACA, and a possible therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Minocycline Reduces Neuronal Death and Attenuates Microglial Response after Pediatric Asphyxial Cardiac Arrest

Tang

Alexander

Clark

et al. 2009

J Cereb Blood Flow Metab

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“…91 Two recent experimental studies have indicated that minocycline could reduce injury volume after MCAO by 2 different methods. 93,94 However, Koistinaho and colleagues demonstrated an inhibition of pro-MMP-2 and pro-MMP-9 expression with a reduction in injury volume after MCAO when either CMT 3 or CMT 8 were applied before, but not after MCAO. 95 Those studies raise the questions to what degree does microglial cell-associated MMP-9 contribute to the injury caused by focal ischemia in rodent models, and whether it is ischemia per se or the consequences of injury to the neurovasculature that leads to microglial activation.…”

Section: Inhibitors Of Mmps In Particular the Modified Tetracyclinesmentioning

confidence: 99%

Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia

Zoppo

Milner

Mabuchi

et al. 2007

Stroke

196

130

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Abstract-Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro-MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors. Key Words: extracellular matrix Ⅲ ischemic stroke Ⅲ matrix metalloproteinases Ⅲ microglia Ⅲ tetracyclines E xtracellular matrix (ECM) glycoproteins participate in the cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system (CNS). Endothelial cells and astrocytes of cerebral capillaries are separated by the basal lamina to whose ECM constituents (eg, collagen type IV, laminins, fibronectin, and heparan sulfate proteoglycans [eg, perlecan]) both cells adhere by specific adhesion receptors. 1-4 Astrocytes and neurons interact directly 5-7 and are themselves stabilized by ECM of a different composition. 8 The association of the microvessel endothelial ECM-astrocyte complex with the neurons they serve comprises a theoretical and possibly functional "neurovascular unit." 3,9 Recent work has demonstrated that during focal ischemia characteristic and rapid changes in both the ECM and the ultrastructural relationships among the cellular components of the neurovascular unit appear. 10 -12 In addition to focal cerebral ischemia, matrix alterations within the CNS occur (1) during acute (eg, infection) or chronic (eg, multiple sclerosis) inflammatory disorders, (2) during invasion by cells with metastatic potential that display anchorageindependent growth, (3) in association with primary tumors of the CNS (eg, gliomas, arteriovenous malformations), and (4) from ...

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“…Furthermore, minocycline may inhibit the activity of matrix metalloproteinases (MMP), diminish permeability of the BBB, inhibit caspase, inducible NO synthase (iNOS) and p38 mitogen-activated protein kinase (MAPK). 134 The neuroprotective efficacy of minocycline has been demonstrated in animal models even when delayed up to 4 h. Minocycline appears to be an ideal neuroprotective candidate based on its established safety profile, good CNS penetration, wide availability, and inexpensive cost, and therefore deserves evaluation in clinical trials of acute ischemic stroke.…”

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confidence: 99%

Clinical trials for cytoprotection in stroke

Labiche

Grotta

2004

Neurotherapeutics

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Summary:To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-totreat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

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Delayed minocycline but not delayed mild hypothermia protects against embolic stroke

Abstract: Background: Inflammatory reactions occurring in the brain after ischemia may contribute to secondary damage. In the present study, effects of minocycline, an anti-inflammatory agent, alone or in combination with mild hypothermia on focal embolic cerebral ischemia have been examined.

Cited by 54 publications

References 21 publications

Minocycline Reduces Neuronal Death and Attenuates Microglial Response after Pediatric Asphyxial Cardiac Arrest

Minocycline Reduces Neuronal Death and Attenuates Microglial Response after Pediatric Asphyxial Cardiac Arrest

Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia

Clinical trials for cytoprotection in stroke

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