Magnesium Deficiency-Dependent Audiogenic Seizures (MDDASs) in Adult Mice: A Nutritional Model for Discriminatory Screening of Anticonvulsant Drugs and Original Assessment of Neuroprotection Properties

Bac, Pierre; Maurois, Pierre; Dupont, Charlotte; Pagès, Nicole; Stables, James P.; Gressèns, Pierre; Evrard, Philippe; Vamecq, Jòseph

doi:10.1523/jneurosci.18-11-04363.1998

Cited by 74 publications

(63 citation statements)

References 67 publications

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“…As previously mentioned, activated mast cells can release several potentially toxic factors including histamine, serotonin, neutral proteases, cytokines, chemokines, and free radicals (18). Although proinflammatory cytokines (11) and free radicals (9,23) have shown toxic effects in the present model, and the participation of other factors cannot be excluded, excess histamine release by IL-9 -activated brain mast cells seems to play a key role in mediating excitotoxic lesion exacerbation by IL-9 pretreatment. Interestingly, antihistamine drugs were neuroprotective only when both H 1 and H 2 histamine receptors were blocked.…”

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confidence: 48%

Deleterious Effects of IL-9–Activated Mast Cells and Neuroprotection by Antihistamine Drugs in the Developing Mouse Brain

et al. 2001

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Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9 -treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9 -treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenateinduced excitotoxic brain lesions in mast cell-deficient P5 pups (WBB6F1/J kit W/W-v ), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9 -treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy. (1-7). Recent hypotheses have implicated multiple preconceptional and prenatal factors, such as hypoxiaperfusion failure, genetic factors, growth factor deficiency, and excess production of cytokines. In a striking retrospective study, mean levels of perinatal circulating cytokines-including IL-1␤, IL-6, IL-8, IL-9, and TNF-␣-were higher in patients with subsequent occurrence of cerebral palsy than in control subjects (8).In that study, although the numbers of included patients were limited, levels of proinflammatory cytokines (IL-1-␤, IL-6, IL-8, and TNF-␣) were associated with one another, but no correlation was detected between IL-9 levels and the levels of the other cytokines tested. Although further studies will be necessary to confirm this initial observation, these data could suggest the existence of a subpopulation of cerebral palsy patients characterized by increased levels of circulating IL-9 at birth. A better understanding of the mechanisms bridging IL-9 blood level elevation and brain damage might open up new therapeutic possibilities for preventing cerebral palsy in infants with high circulating IL-9 levels.Intracerebral injection of ibotenate, a glutamate analog, to newborn mice produces histologic lesions mimicking the brain lesions f...

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Deleterious Effects of IL-9–Activated Mast Cells and Neuroprotection by Antihistamine Drugs in the Developing Mouse Brain

et al. 2001

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“…Hydantoins (imidazolidine-2,4-diones), having a 5-membered ring containing a reactive cyclic urea core, form a wide range of biologically active compounds [1][2][3][4] . Their 2-thioxo analogs, 2-thiohydantoins (2-thioxo-imidazolizin-4-one) also display significant biological activities and are employed as established drugs, fungicides or herbicides [5,6] .…”

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confidence: 99%

Crystal Structures and Conformations of 5-Benzyl-2-thiohydantoin and Its 1-Acetylated Derivative

Kunimoto

Ichitani

Ogawa

et al. 2009

Spectroscopy Letters

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Abstract:The crystal structures of 5-benzyl-2-thiohydantoin (5-BTH) and 1-acetyl-5-benzyl-2-thiohydantoin (1-Ac-5-BTH) have been determined by X-ray diffraction. In the 5-BTH crystals, the enantiomeric (R)-and (S)-5-BTH molecules are connected to form cyclic dimers via the hydrogen bonds of the thioamide and the amide moieties. On the other hand, the intermolecular hydrogen bonds in 1-Ac-5-BTH crystals form an infinite chain. These differences 1 SpectroscLett_kunimoto_revised in the hydrogen bond pattern are also discussed in the IR and Raman spectra. The ab initio molecular orbital calculations (Gaussian 03) with 6-31G(d,p) basis set were carried out for 5-BTH and 1-Ac-5-BTH to get the preferred conformation.

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“…Newborn mice injected intracerebrally with ibotenate, a glutamate analog acting mainly on N-methyl-D-aspartate (NMDA) receptors, develop periventricular cystic white-matter lesions mimicking several aspects of human PVL (10). In this well characterized murine model, several drugs that interfere with the excitotoxic cascade have been shown to be neuroprotective (7,(11)(12)(13)(14) while proinflammatory cytokines (15) and iron (16) exacerbated ibotenateinduced white-matter lesions. In order to further understand the pathophysiology of the ibotenateinduced cystic lesions, we targeted the NMDA receptors thought to be present on white-matter glial cells.…”

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Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Laudenbach¹,

Calò²,

Guerrini³

et al. 2001

J. Clin. Invest.

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IntroductionPeriventricular leukomalacia (PVL) is a hemispheric white-matter lesion that is often cystic and occurs most frequently in infants born before 32 weeks of gestation (1). PVL is the major cause of cerebral palsy among premature infants (2). Based on epidemiological and experimental studies, the pathophysiology of PVL appears to be multifactorial. It potentially involves the combined toxicity of hypoxic-ischemic insults, excess free radicals, maternal-fetal infection with increased cytokine production, and growth factor deficiency (1,(3)(4)(5)(6)(7)(8). Excess release of glutamate and the subsequent overactivation of the excitotoxic cascade could represent a common molecular pathway for several of these risk factors (6, 9).Findings from several experimental studies support this hypothesis. Newborn mice injected intracerebrally with ibotenate, a glutamate analog acting mainly on N-methyl-D-aspartate (NMDA) receptors, develop periventricular cystic white-matter lesions mimicking several aspects of human PVL (10). In this well characterized murine model, several drugs that interfere with the excitotoxic cascade have been shown to be neuroprotective (7,(11)(12)(13)(14) while proinflammatory cytokines (15) and iron (16) exacerbated ibotenateinduced white-matter lesions. In order to further understand the pathophysiology of the ibotenateinduced cystic lesions, we targeted the NMDA receptors thought to be present on white-matter glial cells. Newborn mice were injected intracerebrally with sense, antisense, or missense oligonucleotides specific for the NMDA R1 receptor subunit (P. Gressens, unpublished work). The sequences of the oligonucleotides were identical to those previously used by Wahlestedt et al. in an in vitro assay (17). In newborn mice, pretreatment with antisense oligonucleotides was neuroprotective while control sense oligonucleotides had no effect on the ibotenate-induced lesion. Unexpectedly, missense oligonucleotides, which were used as another control, induced a threefold reduction in the severity of the excitotoxic whitematter lesions. A search of databases with Basic Local Alignment Search Tool (BLAST) revealed that 12 successive nucleotides of the so-called "NMDA R1 missense oligonucleotide" were actually complementary to a triplicated motif of the murine nociceptin (NC) mRNA, suggesting that the blockade of NC production is neuroprotective in the ibotenate model. Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective µ receptor agonist), nor ibot...

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Magnesium Deficiency-Dependent Audiogenic Seizures (MDDASs) in Adult Mice: A Nutritional Model for Discriminatory Screening of Anticonvulsant Drugs and Original Assessment of Neuroprotection Properties

Cited by 74 publications

References 67 publications

Deleterious Effects of IL-9–Activated Mast Cells and Neuroprotection by Antihistamine Drugs in the Developing Mouse Brain

Deleterious Effects of IL-9–Activated Mast Cells and Neuroprotection by Antihistamine Drugs in the Developing Mouse Brain

Crystal Structures and Conformations of 5-Benzyl-2-thiohydantoin and Its 1-Acetylated Derivative

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

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