Minocycline neuroprotection in a rat model of asphyxial cardiac arrest is limited

Keilhoff, Gerburg; Schweizer, Hannes; John, Robin; Langnaese, Kristina; Ebmeyer, Uwe

doi:10.1016/j.resuscitation.2010.11.011

Cited by 16 publications

(10 citation statements)

References 37 publications

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“…Minocycline significantly decreased neuronal degeneration and microglia response (Keilhoff et al . ). However, in a hemorrhagic shock model (incomplete global ischemia), it was interestingly found that minocycline had modest benefit on neurologic outcome in survivors and whether the benefit was because of its inhibition of microglial activation is still open to a question (Drabek et al .…”

Section: Discussionmentioning

confidence: 97%

Inhibition of microglial activation contributes to propofol‐induced protection against post‐cardiac arrest brain injury in rats

Wang

Ling

Feng

et al. 2015

Journal of Neurochemistry

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It has been suggested that propofol can modulate microglial activity and hence may have potential roles against neuroinflammation following brain ischemic insult. However, whether and how propofol can inhibit post-cardiac arrest brain injury via inhibition of microglia activation remains unclear. A rat model of asphyxia cardiac arrest (CA) was created followed by cardiopulmonary resuscitation. CA induced marked microglial activation in the hippocampal CA1 region, revealed by increased OX42 and P2 class of purinoceptor 7 (P2X7R) expression, as well as p38 MAPK phosphorylation. Morris water maze showed that learning and memory deficits following CA could be inhibited or alleviated by pre-treatment with the microglial inhibitor minocycline or propofol. Microglial activation was significantly suppressed likely via the P2X7R/ p-p38 pathway by propofol. Moreover, hippocampal neuronal injuries after CA were remarkably attenuated by propofol. In vitro experiment showed that propofol pre-treatment inhibited ATP-induced microglial activation and release of tumor necrosis factor-a and interleukin-1b. In addition, propofol protected neurons from injury when co-culturing with ATPtreated microglia. Our data suggest that propofol pre-treatment inhibits CA-induced microglial activation and neuronal injury in the hippocampus and ultimately improves cognitive function.

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Section: Discussionmentioning

confidence: 97%

Inhibition of microglial activation contributes to propofol‐induced protection against post‐cardiac arrest brain injury in rats

Wang

Ling

Feng

et al. 2015

Journal of Neurochemistry

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“…56 One study reported a positive effect of minocycline but not hypothermia after focal brain ischemia in adult rats. 33 These effects were suggested to be mediated by microglia, 26 or independent of microglia.…”

Section: Discussionmentioning

confidence: 99%

Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats

Drábek¹,

Janata²,

Wilson³

et al. 2014

Resuscitation

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Neuro-cognitive disabilities are a well-recognized complication of hypothermic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and microglial proliferation and activation that are only partially mitigated by hypothermia. Microglia, and possibly other cells, are suggested to elaborate tumor necrosis factor alpha (TNF-α) which can trigger neuronal death cascades and exacerbate edema after CNS insults. Minocycline is neuroprotective in some brain ischemia models in part by blunting the microglial response. We tested the hypothesis that minocycline would attenuate neuroinflammation as reflected by brain tissue levels of TNF-α after hypothermic CA in rats. Rats were subjected to rapid exsanguination, followed by a 6 min normothermic CA. Hypothermia (30 °C) was then induced by an aortic saline flush. After a total of 20 min CA, resuscitation was achieved via cardiopulmonary bypass (CPB). After 5 min reperfusion, minocycline (90 mg/kg; n=6) or vehicle (PBS; n=6) were given. Hypothermia (34 °C) was maintained for 6 h. Rats were sacrificed at 6 or 24 h. TNF-α was quantified (ELISA) in four brain regions (cerebellum, CEREB; cortex, CTX; hippocampus, HIP; striatum, STRI). Naïve rats (n=6) and rats subjected to the same anesthesia and CPB but no CA served as controls (n=6). Immunocytochemistry was used to localize TNF-α. Naïve rats and CPB controls had no detectable TNF-α in any brain region. CA markedly increased brain TNF-α. Regional differences were seen, with the highest TNF-α levels in striatum in CA groups (10-fold higher, P<0.05 vs. all other brain regions). TNF-α was undetectable at 24 h. Minocycline attenuated TNF-α levels in CTX, HIP and STRI (P<0.05). TNF-α showed unique co-localization with neurons. In conclusion, we report region-dependent early increases in brain TNF-α levels after prolonged hypothermic CA, with maximal increases in striatum. Surprisingly, TNF-α co-localized in neurons and not microglia. Minocycline attenuated TNF-α by approximately 50% but did not totally ablate its production. That minocycline decreased brain TNF-α levels suggests that it may represent a therapeutic adjunct to hypothermia in CA neuroprotection. University of Pittsburgh IACUC 0809278B-3.

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“…Minocycline is a second-generation semisynthetic tetracycline antibiotic that has unusual anti-inflammatory properties (Dheen et al,2007). Cell culture and animal experiments have demonstrated that minocycline readily crosses the blood-brain barrier and attenuates microglial cell activation and limits production of inflammatory mediators in a number of conditions (Chen-Roetling et al,2009; Keilhoff et al,2011). For instance, minocycline pretreatment of BV-2 (microglia) cultures decreased LPS-stimulated cytokine production (Horvath et al,2008).…”

Section: Discussionmentioning

confidence: 99%

Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes

2012

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Systemic injection of lipopolysaccharide (LPS) induces a robust immune response as well as thermal and mechanical hyperalgesia. Spinal and peripheral glial cells have been implicated as important mediators in this hyperalgesia but the specific contributions of microglia versus astrocytes are not entirely clear. To better define these mechanisms, this study examined the febrile response, nociceptive sensitivity, glial cell reactivity and cytokine production in the dorsal root ganglion (DRG) and spinal cord in rats following systemic treatment with LPS and the effects of minocycline in countering these responses. Intraperitoneal LPS injection resulted in an increase in core body temperature and produced hyperalgesia to heat and mechanical stimuli. Western blot studies revealed increased expression of microgial cell, macrophage and satellite cell markers in DRG and microglial and astrocyte markers in spinal cord following LPS treatment. Real-time RT-PCR indicated that LPS treatment increased cytokine mRNA expression levels in both the DRG and the spinal cord. Minocycline suppressed all LPS-induced behavioral effects but not the febrile response. Moreover, minocycline prevented LPS induced microglia/macrophage activation and cytokine responses in spinal cord and DRG, but did not affect the activation of astrocytes/satellite cells. These data demonstrate that LPS-induced changes in nociceptive sensitivity are likely mediated by activation of microglial cells and/or macrophages in the spinal cord and DRG.

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Minocycline neuroprotection in a rat model of asphyxial cardiac arrest is limited

Cited by 16 publications

References 37 publications

Inhibition of microglial activation contributes to propofol‐induced protection against post‐cardiac arrest brain injury in rats

Inhibition of microglial activation contributes to propofol‐induced protection against post‐cardiac arrest brain injury in rats

Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats

Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes

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