Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model

Tsuji, Masahiro; Wilson, Mary Ann; Lange, Mary S.; Johnston, Michael V.

doi:10.1016/j.expneurol.2004.01.011

Cited by 173 publications

(108 citation statements)

References 45 publications

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“…Evidence suggests that neuroinflammation is a negative regulator of neurogenesis (Monje et al, 2003). Furthermore, treatment with minocycline after HI reduced microglia activation and injury in the immature brain (Arvin et al, 2002;Cai et al, 2006;Fox et al, 2005) although conflicting reports exist (Tsuji et al, 2004). Further work is needed to elucidate the roles of microglia and consequences of inflammation after HI, but injury-induced inflammation may be an important target for therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

et al. 2011

J Cereb Blood Flow Metab

105

112

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The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxicischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72 hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4 ± 14.6 mm 3 in controls (n = 15) to 27.6 ± 6.2 mm 3 in lithium-treated animals (n = 14) 7 weeks after HI (P < 0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1b and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72 hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.

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Section: Discussionmentioning

confidence: 99%

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

et al. 2011

J Cereb Blood Flow Metab

105

112

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“…However, recent investigations in animal models of Huntington's disease (HD), Parkinson's disease and hypoxicischemic brain injury in neonates, have shown minocycline to be ineffective, increasing morbidity and mortality, and it is plausible that the variable and sometimes negative effect of minocycline is related to mode of administration and dose used (Diguet et al, 2004;Smith et al, 2003;Tsuji et al, 2004;Yang et al, 2003). High animal dosing, up to 180 mg/kg, has been employed to reach maximal penetration of the drug into the CNS (Yrjanheikki et al, 1998) or in order to inhibit cyt c release post injury (Teng et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Månsson¹,

Hansson²,

Morota³

et al. 2007

Neurobiology of Disease

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Minocycline has been shown to be neuroprotective in ischemic and neurodegenerative disease models and could potentially be relevant for clinical use. We revisited the hypothesis that minocycline acts through direct inhibition of calcium-induced mitochondrial permeability transition (mPT) resulting in reduced release of cytochrome c (cyt c). Minocycline, at high dosage, was found to prevent calcium-induced mitochondrial swelling under energized conditions similarly to the mPT inhibitor cyclosporin A (CsA) in rodent mitochondria derived from the CNS. In contrast to CsA, minocycline dose-dependently reduced mitochondrial calcium retention capacity (CRC) and respiratory control ratios and was ineffective in the de-energized mPT assay. Further, minocycline did not inhibit calcium-or tBid-induced cyt c release. We conclude that the neuroprotective mechanism of minocycline is likely not related to direct inhibition of mPT and propose that the mitochondrial effects of minocycline may contribute to toxicity rather than tissue protection at high dosing in animals and humans.

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“…There is clearly a benefit to risk assessment with all agents that are likely to have protective effects, and careful study in animal models as well as follow-up in human trials is warranted. The antibiotic minocycline, which is protective in some models of brain injury, can also enhance injury in neonatal hypoxia-ischemia (93). The observation that signaling pathways involved in cell death are sexually dimorphic is also important both for pre-clinical studies and clinical trials.…”

Section: Neuroprotective Therapies For Brain Injurymentioning

confidence: 99%

Plasticity and injury in the developing brain

Johnston¹,

Ishida²,

Ishida³

et al. 2009

Brain and Development

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The child's brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders. KeywordsPlasticity; Injury; Fragile X Syndrome; Rett Syndrome; Hypoxia-Ischemia; NMDA; AMPA; Periventricular Leukomalacia Many disorders and injuries of the developing brain affect the basic mechanisms that allow the nervous system to be shaped by experience during childhood. These mechanisms provide the substrate for brain plasticity (kasosei in Japanese), which is much more active in children than in adults. Plasticity in the child's brain is enhanced because the organization of networks of *Correspondence: 707 North Broadway, Baltimore, MD 21205, Fax: 443-923-9317 Phone: 443-923-9315, Johnston@kennedykrieger.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. neuronal synapses as well as white matter pathways remain "under construction" well into adolescence and even later(1). Accordingly, the effects of intensive learning in school, exposure to a second language or practice in athletics has a much greater impact on children than adults. Several neurobiological mechanism contribute to brain plasticity, including an over-production of neurons in early development, apoptosis or programmed cell death of excessive neurons, overproduction and elimination of immature synapses in childhood, and continuous stabilization and strengthening of synaptic connections later in life(2). In this review we focus on some mechanisms for synaptic plasticity, and emerging evidence that these processes are disrupted in several pediatric neurological disorders. NIH Public Access Synaptic PlasticitySynaptic p...

show abstract

Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model

Cited by 173 publications

References 45 publications

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Plasticity and injury in the developing brain

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