MRI study on delayed ancrod therapy of focal cerebral ischaemia in rats

Elger, Bernd; Hornberger, Wilfried; Schwarz, Margarete

doi:10.1016/s0014-2999(97)01217-x

Cited by 10 publications

(4 citation statements)

References 31 publications

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“…Similar methods have been used to measure lesion volumes after TBI in humans (38) as well as after cerebral ischemia in rats (39). We have found that such MRI lesion volume measurements correlate significantly with histologic lesion volume measurements using stereology (in preparation).…”

Section: Neurologic Scoringmentioning

confidence: 69%

Presence of DNA Fragmentation and Lack of Neuroprotective Effect in DFF45 Knockout Mice Subjected to Traumatic Brain Injury

Yakovlev

Movsesyan

et al. 2001

Mol Med

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Background: Apoptosis plays an important pathophysiologic role in neuronal cell loss and associated neurologic deficits following traumatic brain injury (TBI). DNA fragmentation represents one of the characteristic biochemical features of neuronal apoptosis and is observed after experimental TBI. DFF45 and DFF40 are essential for DNA fragmentation in various models of apoptosis. Materials and Methods: We used mice deficient in DFF45 and wild-type controls. Oligonucleosomal DNA fragmentation induced by TBI was analyzed using in vivo and in vitro assays. Expression and integrity of DFF45 and DFF40 proteins was assessed by Western analysis. Other outcome measurements included neurologic scoring, learning/memory tests, lesion volume measurements (MRI), and assessment of cell viability in vitro among others. Results: We compared the effects of controlled cortical impact (CCI) trauma in DFF45 knockout mice and wild-type controls. Analysis of TBI-induced DNA fragmentation in brain cortex from wild-type and DFF45 knockout mice indicates that, although somewhat delayed, oligonucleoso-Address correspondence and reprint requests to: A.I. Faden, MD, mal cleavage of DNA occurs after TBI in DFF45 knockout mice. DFF45 knockouts showed no significant differences in behavioral outcomes or lesion volumes after TBI as compared to wild-type controls. Using an in vitro reconstitution system, we also demonstrated that cleavage of DFF45 by caspase-3 is not sufficient for DNA fragmentation induced by protein extracts from rat brain cortex. We found that endonuclease activity induced in rat brain cortex following TBI depends on the presence of Mg 2ϩ and Ca 2ϩ , but is not inhibited by Zn 2ϩ . Primary neuronal cultures from DFF45 knockouts failed to show DNA laddering in response to staurosporine, but did show prominent, albeit delayed, DNA fragmentation following treatment with etoposide. In contrast, primary neurons from wildtype animals demonstrated marked DNA fragmentation following treatment with staurosporine or etoposide. Conclusions:The results of this study suggest that, in addition to DFF45/40, other endonucleases may be essential for chromatin degradation during neuronal apoptosis in adult brain after TBI.

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Section: Neurologic Scoringmentioning

confidence: 69%

Presence of DNA Fragmentation and Lack of Neuroprotective Effect in DFF45 Knockout Mice Subjected to Traumatic Brain Injury

Yakovlev

Movsesyan

et al. 2001

Mol Med

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“…One such protease, Ancrod, derived from Malayan pit viper venom, cleaves Fg␣ and rapidly decreases plasma Fg levels (22). It effectively limited infarct size in acute stroke animal models (21), and two of three randomized controlled clinical trials involving acute stroke patients showed positive results (8a, 54). While lack of beneficial effect, increased mortality, and symptomatic intracranial hemorrhage in one study (33) completely stopped drug production, post hoc analysis suggested that more carefully supervising dosing regimens and patient stratification could have achieved efficacy and reduced hemorrhagic events (40).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Craciun

Ajay

Hoffmann

et al. 2014

American Journal of Physiology-Renal Physiology

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Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (∼75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.

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“…In addition, posttreatment of compound 14a was studied in the rat model of proximal middle cerebral artery (MCA) occlusion. This animal model has been shown to have a predictive value for stroke in humans because beneficial drug effects after permanent MCA occlusion in rats were reflected in a positive outcome of a phase III clinical trial. , For appropriate dosing of 14a in the in vivo studies, the pharmacokinetics properties of the compound were evaluated. Finally, potential hypothermic activity of 14a was assessed in rats, which could eventually account for indirect neuroprotective effects.…”

Section: Pharmacologymentioning

confidence: 99%

Novel α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA) Receptor Antagonists of 2,3-Benzodiazepine Type: Chemical Synthesis, in Vitro Characterization, and in Vivo Prevention of Acute Neurodegeneration

et al. 2005

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Under pathophysiological conditions, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor activation is considered to play a key role in several disorders of the central nervous system. In the search for AMPA receptor antagonists, the synthesis and pharmacological characterization of a series of novel compounds that are structurally related to GYKI 52466 (1), a well-known selective noncompetitive AMPA receptor antagonist, was performed. In vitro, 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638, 14a) antagonized the kainate-induced currents in cultured hippocampal neurons with an IC(50) of 3.4 microM in a noncompetitive fashion. When tested in a clinically predictive rat model of acute ischemic stroke, this noncompetitive AMPA receptor antagonist significantly reduced brain infarction, indicating that it is neuroprotective after permanent focal cerebral ischemia.

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MRI study on delayed ancrod therapy of focal cerebral ischaemia in rats

Cited by 10 publications

References 31 publications

Presence of DNA Fragmentation and Lack of Neuroprotective Effect in DFF45 Knockout Mice Subjected to Traumatic Brain Injury

Presence of DNA Fragmentation and Lack of Neuroprotective Effect in DFF45 Knockout Mice Subjected to Traumatic Brain Injury

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Novel α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA) Receptor Antagonists of 2,3-Benzodiazepine Type: Chemical Synthesis, in Vitro Characterization, and in Vivo Prevention of Acute Neurodegeneration

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