Suppression of microglia activation after hypoxia–ischemia results in age-dependent improvements in neurologic injury

Çıkla, Ulaş; Chanana, Vishal; Kintner, Douglas B.; Covert, Lucia; Dewall, Taylor; Waldman, Alex; Rowley, Paul A.; Cengiz, Pelin; Ferrazzano, Peter

doi:10.1016/j.jneuroim.2015.12.004

Cited by 28 publications

(37 citation statements)

References 45 publications

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“…Consistent with these observations, minocycline did not affect motor deficits in brain-injured adult mice (Bye et al, 2007) or spatial learning and memory following HI in neonatal mice (Cikla et al, 2016) and TBI in adult rats (Kelso et al, 2011). This lack of sustained effect may be due to the fact that the half-life of minocycline in rodents is rather short (2–3 hours) (Andes and Craig, 2002).…”

Section: Discussionsupporting

confidence: 70%

“…Short-term administration of minocycline (similar to the paradigm used in study 1) has been found effective in decreasing microglial activation following neonatal hypoxic ischemia (Cai et al, 2006; Cikla et al, 2016; Fan et al, 2006; Lechpammer et al, 2008), pediatric cardiac arrest (Tang et al, 2010), neonatal repetitive TBI (Hanlon et al, 2016), and adult TBI (Bye et al, 2007; Homsi et al, 2010; Siopi et al, 2011). The reduction in activated microglia was accompanied by an attenuation of neuronal damage (Cikla et al, 2016), a decrease in asphyxia-induced neurodegeneration (Tang et al, 2010), and a reduction of lesion volume following TBI (Homsi et al, 2010).…”

Section: Discussionmentioning

confidence: 96%

“…The reduction in activated microglia was accompanied by an attenuation of neuronal damage (Cikla et al, 2016), a decrease in asphyxia-induced neurodegeneration (Tang et al, 2010), and a reduction of lesion volume following TBI (Homsi et al, 2010). However, the association between microglial activation and attendant neurodegeneration in brain injury is not quite clear-cut: minocycline treatment following TBI in the adult mouse decreased F4/80-labeled microglia that exhibited the activated phenotype without affecting lesion volume or TUNEL labeling (Bye et al, 2007) whereas in a model of neonatal stroke minocycline failed to reduce microglial activation, but still had a beneficial effect on lesion volume (Fox et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Following neonatal rodent models of HI, minocycline decreased microglial activation which was associated with a reduction in injury-induced neuronal damage, oligodendroglial cell death, hypomyelination, white matter atrophy and locomotor deficits (Cai et al, 2006; Carty et al, 2008; Cikla et al, 2016; Fan et al, 2006). In a model of pediatric cardiac arrest, acute treatment with minocycline reduced microglial activation along with neurodegeneration and apoptosis (Tang et al, 2010).…”

Section: Introductionmentioning

confidence: 98%

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Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat

Hanlon

Raghupathi

Huh

2017

Experimental Neurology

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The role of microglia in the pathophysiology of injury to the developing brain has been extensively studied. In children under the age of 4 who have sustained a traumatic brain injury (TBI), markers of microglial/macrophage activation were increased in the cerebrospinal fluid and were associated with worse neurologic outcome. Minocycline is an antibiotic that decreases microglial/macrophage activation following hypoxic-ischemia in neonatal rodents and TBI in adult rodents thereby reducing neurodegeneration and behavioral deficits. In study 1, 11-day-old rats received an impact to the intact skull and were treated for 3 days with minocycline. Immediately following termination of minocycline administration, microglial reactivity was reduced in the cortex and hippocampus (p<0.001) and was accompanied by an increase in the number of fluoro-Jade B profiles (p<0.001) suggestive of a reduced clearance of degenerating cells; however, this effect was not sustained at 7 days post-injury. Although microglial reactivity was reduced in the white matter tracts (p<0.001), minocycline treatment did not reduce axonal injury or degeneration. In the thalamus, minocycline treatment did not affect microglial reactivity, axonal injury and degeneration, and neurodegeneration. Injury-induced spatial learning and memory deficits were also not affected by minocycline. In study 2, to test whether extended dosing of minocycline may be necessary to reduce the ongoing pathologic alterations, a separate group of animals received minocycline for 9 days. Immediately following termination of treatment, microglial reactivity and neurodegeneration in all regions examined were exacerbated in minocycline-treated brain-injured animals compared to brain-injured animals that received vehicle (p<0.001), an effect that was only sustained in the cortex and hippocampus up to 15 days post-injury (p<0.001). Whereas injury-induced spatial learning deficits remained unaffected by minocycline treatment, memory deficits appeared to be significantly worse (p<0.05). Sex had minimal effects on either injury-induced alterations or the efficacy of minocycline treatment. Collectively, these data demonstrate the differential effects of minocycline in the immature brain following impact trauma and suggest that minocycline may not be an effective therapeutic strategy for TBI in the immature brain.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat

Hanlon

Raghupathi

Huh

2017

Experimental Neurology

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“…Although the localization of the injury depends on the gestational age and the duration and the severity of the insult, hippocampus is one of the most commonly effected regions in the CNS after term neonatal HI, and increased hippocampal astrogliosis has been confirmed by up-regulation of the Glial Fibrillary Acidic Protein (GFAP) 3 d after the neonatal HI 7,10,12,13 . Sex differences in astrocyte function were shown in both neonates and adult rodents after cerebral ischemia 14,15 .…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Mouse Hippocampal Astrocytes after <em>In-Vitro</em> Ischemia

Chanana

Tümtürk

Kintner

et al. 2016

JoVE

Self Cite

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Astrogliosis following hypoxia/ischemia (HI)-related brain injury plays a role in increased morbidity and mortality in neonates. Recent clinical studies indicate that the severity of brain injury appear to be sex dependent, and that the male neonates are more susceptible to the effects of HI-related brain injury, resulting in more severe neurological outcomes as compared to females with comparable brain injuries. The development of reliable methods to isolate and maintain highly enriched populations of sexed hippocampal astrocytes is essential to understand the cellular basis of sex differences in the pathological consequences of neonatal HI. In this study, we describe a method for creating sex specific hippocampal astrocyte cultures that are subjected to a model of in-vitro ischemia, oxygen-glucose deprivation, followed by reoxygenation. Subsequent reactive astrogliosis was examined by immunostaining for the Glial Fibrillary Acidic Protein (GFAP) and S100B. This method provides a useful tool to study the role of male and female hippocampal astrocytes following neonatal HI, separately. Video LinkThe video component of this article can be found at

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Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain

Strahan

Walker

Montgomery

et al. 2016

Developmental Neurobiology

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Minocycline, an antibiotic of the tetracycline family, inhibits microglia in many paradigms, and is among the most commonly used tools for examining the role of microglia in physiological processes. Microglia may play an active role in triggering developmental neuronal cell death, although findings have been contradictory. To determine whether microglia influence developmental cell death, we treated perinatal mice with minocycline (45 mg/kg) and quantified effects on dying cells and microglial labeling using immunohistochemistry for activated caspase-3 (AC3) and ionized calcium-binding adapter molecule 1 (Iba1), respectively. Contrary to our expectations, minocycline treatment from embryonic day 18 to postnatal day (P)1 caused a >10-fold increase in cell death 8 h after the last injection in all brain regions examined, including the primary sensory cortex (S1), septum, hippocampus and hypothalamus. Iba1 labeling was also increased in most regions. Similar effects, although of smaller magnitude, were seen when treatment was delayed to P3-P5. Minocycline treatment from P3-P5 also decreased overall cell number in the septum at weaning, suggesting lasting effects of the neonatal exposure. When administered at lower doses (4.5 or 22.5 mg/kg), or at the same dose one week later (P10-P12), minocycline no longer increased microglial markers or cell death. Taken together, the most commonly used microglial “inhibitor” increases cell death and Iba1 labeling in the neonatal mouse brain. Minocycline is used clinically in infant and pediatric populations; caution is warrented when using minocycline in developing animals, or extrapolating the effects of this drug across ages.

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Suppression of microglia activation after hypoxia–ischemia results in age-dependent improvements in neurologic injury

Cited by 28 publications

References 45 publications

Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat

Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat

Sex Differences in Mouse Hippocampal Astrocytes after <em>In-Vitro</em> Ischemia

Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain

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