Plasminogen Activator Inhibitor-1 Mitigates Brain Injury in a Rat Model of Infection-Sensitized Neonatal Hypoxia-Ischemia

Yang, Dianer; Sun, Yu; Nemkul, Niza; Baumann, Jessica M.; Shereen, A. Duke; Dunn, Richard S.; Wills‐Karp, Marsha; Lawrence, Daniel A.; Lindquist, Diana M.; Kuan, Chia Yi

doi:10.1093/cercor/bhs115

Cited by 35 publications

(46 citation statements)

References 46 publications

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“…Activation of microglia and innate immunity is considered a major component contributing to immature brain injury (55,56). sPIF treatment resulted in reduced microglial activation (Fig.…”

Section: Discussionmentioning

confidence: 99%

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Mueller

Zhou

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extra-cellular micro-RNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage.Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/ let-7 regulatory axis also may operate during embryo implantation and development.

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“…Activation of microglia and innate immunity is considered a major component contributing to immature brain injury (55,56). sPIF treatment resulted in reduced microglial activation (Fig.…”

Section: Discussionmentioning

confidence: 99%

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Mueller

Zhou

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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“…121,122 Other studies have shown that inhibition of inflammation by intracerebroventricular injection of a stable, mutant form of plasminogen activator protein-1, given up to 4 hours after the onset of LPS-sensitized hypoxia-ischaemia, reduced hypoxia-ischaemia-induced blood-brain barrier damage, microglial activation, and brain tissue loss. 123 Furthermore, we recently demonstrated that blocking sensitizing inflammation with a novel class of innate defence regulator peptide (IDR-1018) provided marked neuroprotection and modulated inflammation. This effect was observed even when the peptide was given 3 hours after the induction of LPS-sensitized hypoxia-ischaemia.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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“…Transient hypoxic ischemia (tHI), which was applied 45 min after HI, followed by reperfusion in neonatal rat brains was performed as previously described, with minor modifications (37,38). Since we found that GAP43-gephyrin interaction was induced during the reoxygenation/reperfusion period in the in vitro tHI (see Fig.…”

Section: S41amentioning

confidence: 99%

Protein Kinase C-Dependent Growth-Associated Protein 43 Phosphorylation Regulates Gephyrin Aggregation at Developing GABAergic Synapses

Wang

H²,

Song

et al. 2015

Molecular and Cellular Biology

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g Growth-associated protein 43 (GAP43) is known to regulate axon growth, but whether it also plays a role in synaptogenesis remains unclear. Here, we found that GAP43 regulates the aggregation of gephyrin, a pivotal protein for clustering postsynaptic GABA A receptors (GABA A Rs), in developing cortical neurons. Pharmacological blockade of either protein kinase C (PKC) or neuronal activity increased both GAP43-gephyrin association and gephyrin misfolding-induced aggregation, suggesting the importance of PKC-dependent regulation of GABAergic synapses. Furthermore, we found that PKC phosphorylation-resistant GAP43 S41A , but not PKC phosphorylation-mimicking GAP43 S41D , interacted with cytosolic gephyrin to trigger gephyrin misfolding and its sequestration into aggresomes. In contrast, GAP43 S41D , but not GAP43 S41A , inhibited the physiological aggregation/clustering of gephyrin, reduced surface GABA A Rs under physiological conditions, and attenuated gephyrin misfolding under transient oxygen-glucose deprivation (tOGD) that mimics pathological neonatal hypoxia. Calcineurin-mediated GAP43 dephosphorylation that accompanied tOGD also led to GAP43-gephyrin association and gephyrin misfolding. Thus, PKC-dependent phosphorylation of GAP43 plays a critical role in regulating postsynaptic gephyrin aggregation in developing GABAergic synapses. Proper development of inhibitory GABAergic synapses is critical for establishing an excitatory/inhibitory balance in the neural network (1, 2). The impairment of postsynaptic GABA A receptor (GABA A R) activity is a major cause of neuronal hyperactivity, affecting cognitive development and psychosocial behaviors (3, 4). Postsynaptic surface insertion and clustering of GABA A Rs determine the efficacy of GABAergic synapses (4, 5). Gephyrin, a microtubule-associated protein, is a key scaffolding protein that requires the GABA A R ␥2 subunit for clustering GABA A Rs at the postsynaptic membrane (6, 7). The lack of neuronal gephyrin reduces postsynaptic GABA A R clustering, thereby impairing inhibitory synaptic transmission (8, 9).In central neurons, gephyrin monomers oligomerize to form a hexagonal lattice, also called gephyrin clusters, underneath the cell surface membrane to anchor postsynaptic GABA A Rs (10). However, numerous studies have shown that gephyrin is an aggregation-prone protein that forms large clumps when expressed in nonneural cells or cell-free systems (11, 12). Instead, gephyrin in neurons forms small aggregates/clusters in both the cytosol and submembrane domain for receptor clustering, suggesting a neuronal machinery that regulates gephyrin clustering. To date, a postsynaptic protein, collybistin, a GDP-GTP exchanging factor, is the only gephyrin-interacting protein that can effectively disperse gephyrin clumps into oligomeric clusters in HEK293T cells (13). Gephyrin scaffolding in neurons depends on the dynamic rearrangement of microtubules and actin microfilaments at postsynaptic sites (14,15). Whether cytoskeleton-associated proteins are involved in regulat...

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Plasminogen Activator Inhibitor-1 Mitigates Brain Injury in a Rat Model of Infection-Sensitized Neonatal Hypoxia-Ischemia

Cited by 35 publications

References 46 publications

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Inflammation‐induced sensitization of the brain in term infants

Protein Kinase C-Dependent Growth-Associated Protein 43 Phosphorylation Regulates Gephyrin Aggregation at Developing GABAergic Synapses

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