Olomoucine

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Miroslav Strnad - One of the best experts on this subject based on the ideXlab platform.

  • LEADING ARTICLE Antiproliferative effect of plant cytokinin analogues with an inhibitory activity on cyclin-dependent kinases
    2020
    Co-Authors: K Vermeulen, Miroslav Strnad, M Lenjou, G Nijs, I Rodrigus, B Stockman, H Van Onckelen, Van Bockstaele
    Abstract:

    In this study, analogues of Olomoucine, a previously described plant cytokinin analogue with cyclin-dependent kinase (CDK) inhibitory activity, were investigated for effect on CDK1 and CDK2 and for effect on cell proliferation. Eight new compounds exhibit stronger inhibitory activity on CDK1 and CDK2 and on cell proliferation than Olomoucine. Some active compounds showed low inhibition of proliferation of normal myeloid growth. Improvement of inhibitory activity of known compounds with a C6-benzylamino group was brought about by substitution with one hydroxyl. Also, new C2 substituents associated with inhibitory activity on CDK and on cell proliferation are described. There was a significant correlation between effect on CDK and antiproliferative effect on the KG1 and Molt3 cell lines and on primary human lymphocytes, strongly suggesting that at least part of the antiproliferative effect of cytokinin analogues was due to inhibition of CDK activity. Cytokinin analogues induced apoptosis in a time- and concentration-dependent manner and changes in cell cycle distribution. The antiproliferative and pro-apoptotic effects of plant cytokinin analogues suggest that they are a new class of cytostatic agents and that they may find an application in the chemotherapy of cancer.

  • Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy.
    PLOS ONE, 2014
    Co-Authors: Jitka Holcakova, Miroslav Strnad, Peter Tomasec, Roman Hrstka, Vladimir Krystof, Petr Muller, Marta Nekulova, Gavin William Grahame Wilkinson, Borivoj Vojtesek
    Abstract:

    Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II mediated transcription. Several pharmacological CDK inhibitors are currently in clinical trials as potential cancer therapeutics and some of them also exhibit antiviral effects. Olomoucine II and roscovitine, purine-based inhibitors of CDKs, were described as effective antiviral agents that inhibit replication of a broad range of wild type human viruses. Olomoucine II and roscovitine show high selectivity for CDK7 and CDK9, with important functions in the regulation of RNA polymerase II transcription. RNA polymerase II is necessary for viral transcription and following replication in cells. We analyzed the effect of inhibition of CDKs by Olomoucine II on gene expression from viral promoters and compared its effect to widely-used roscovitine. We found that both roscovitine and Olomoucine II blocked the phosphorylation of RNA polymerase II C-terminal domain. However the repression of genes regulated by viral promoters was strongly dependent on gene localization. Both roscovitine and Olomoucine II inhibited expression only when the viral promoter was not integrated into chromosomal DNA. In contrast, treatment of cells with genome-integrated viral promoters increased their expression even though there was decreased phosphorylation of the C-terminal domain of RNA polymerase II. To define the mechanism responsible for decreased gene expression after pharmacological CDK inhibitor treatment, the level of mRNA transcription from extrachromosomal DNA was determined. Interestingly, our results showed that inhibition of RNA polymerase II C-terminal domain phosphorylation increased the number of transcribed mRNAs. However, some of these mRNAs were truncated and lacked polyadenylation, which resulted in decreased translation. These results suggest that phosphorylation of RNA polymerase II C-terminal domain is critical for linking transcription and posttrancriptional processing of mRNA expressed from extrachromosomal DNA.

  • the inhibitor of cyclin dependent kinases Olomoucine ii exhibits potent antiviral properties
    Antiviral Chemistry & Chemotherapy, 2010
    Co-Authors: Jitka Holcakova, Miroslav Strnad, Peter Tomasec, Joachim Jakob Bugert, Eddie Cy Wang, Gavin W G Wilkinson, Roman Hrstka, Vladimir Krystof, Borivoj Vojtesek
    Abstract:

    Background:Olomoucine II, the most recent derivative of roscovitine, is an exceptionally potent pharmacological inhibitor of cyclin-dependent kinase activities. Here, we report that Olomoucine II is also an effective antiviral agent.Methods:Antiviral activities of Olomoucine II were tested on a range of human viruses in in vitro assays that evaluated viral growth and replication.Results:Olomoucine II inhibited replication of a broad range of wild-type human viruses, including herpes simplex virus, human adenovirus type-4 and human cytomegalovirus. Olomoucine II also inhibited replication of vaccinia virus and herpes simplex virus mutants resistant to conventional acyclovir treatment. This report is the first demonstration of a poxvirus being sensitive to a cyclin-dependent kinase inhibitor. The antiviral effects of Olomoucine II could be observed at lower concentrations than with roscovitine, although both were short-term. A remarkable observation was that Olomoucine II, when used in combination with the ...

  • interactions of Olomoucine ii with human liver microsomal cytochromes p450
    Drug Metabolism and Disposition, 2009
    Co-Authors: Michal Siller, Pavel Anzenbacher, Eva Anzenbacherova, Karel Dolezal, Igor Popa, Miroslav Strnad
    Abstract:

    Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of Olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an Olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N 6 -benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of Olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.

  • antiproliferative activity of Olomoucine ii a novel 2 6 9 trisubstituted purine cyclin dependent kinase inhibitor
    Cellular and Molecular Life Sciences, 2005
    Co-Authors: Vladimir Krystof, Libor Havlicek, I W Mcnae, Malcolm D Walkinshaw, Peter M Fischer, Petr Muller, B Vojtěsek, M Orsag, Miroslav Strnad
    Abstract:

    The study describes the protein kinase selectivity profile, as well as the binding mode of Olomoucine II in the catalytic cleft of CDK2, as determined from cocrystal analysis. Apart from the main cell cycle-regulating kinase CDK2, Olomoucine II exerts specificity for CDK7 and CDK9, with important functions in the regulation of RNA transcription. In vitro anticancer activity of the inhibitor in a panel of tumor cell lines shows a wide potency range with a slight preference for cells harboring a wild-type p53 gene. Cell-based assays confirmed activation of p53 protein levels and events leading to accumulation of p21WAF1. Additionally, in Olomoucine II-treated cells, Mdm2 was found to form a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase function. We conclude that perturbations in RNA synthesis may lead to activation of p53 and that this contributes to the antiproliferative potency of cyclindependent kinase inhibitors.

Laurent Meijer - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis of a new series of purine derivatives and their anti‐cyclin‐dependent kinase activities
    Journal of Heterocyclic Chemistry, 2009
    Co-Authors: Michel Legraverend, Sophie Leclerc, Odile Ludwig, Laurent Meijer
    Abstract:

    The synthesis of new purine derivatives designed to inhibit cell cycle regulating cyclin-dependent kinases (CDKs), is reported. These compounds, related to Olomoucine and roscovitine, are characterised by the presence of apyrrolidine methanol substituent at C-2 and a variety of ortho, meta and/or para substituents on the C-6 arylamino group.

  • Synthesis of a new series of purine derivatives and their anti-cyclin-dependent kinase activities
    Journal of Heterocyclic Chemistry, 2001
    Co-Authors: Michel Legraverend, Sophie Leclerc, Odile Ludwig, Laurent Meijer
    Abstract:

    The synthesis of new purine derivatives designed to inhibit cell cycle regulating cyclin-dependent kinases (CDKs), is reported. These compounds, related to Olomoucine and roscovitine, are characterised by the presence of apyrrolidine methanol substituent at C-2 and a variety of ortho, meta and/or para substituents on the C-6 arylamino group.

  • In Vitro Evaluation of a Novel 2,6,9-Trisubstituted Purine Acting As a Cyclin-Dependent Kinase Inhibitor
    Annals of the New York Academy of Sciences, 1999
    Co-Authors: N. Giocanti, Sophie Leclerc, Laurent Meijer, Michel Legraverend, Odile Ludwig, Emile Bisagni, Ramin Sadri, Vincent Favaudon
    Abstract:

    NICOLE GIOCANTI,a RAMIN SADRI,a MICHEL LEGRAVEREND,b ODILE LUDWIG,b EMILE BISAGNI,bSOPHIE LECLERC,c LAURENT MEIJER,c AND VINCENT FAVAUDONa.d aU 350 INSERM and bUMR 176 CNRS, Institut Curie, Centre Universitaire, 91405 Orsay, France cUPR 9042 CNRS, Station Biologique, 29682 Roscoff, France The frequent deregulation of cell cycle progression in cancer1 has prompted an active search for kinase inhibitors with high affinity and specificity for cyclin-dependent kinases (Cdks). Three major classes of Cdk-targeting drugs have been identified to date, including butyrolactone I,2 polyhydroxylated flavones such as flavopiridol,3 and substituted purines.4 The first substituted purine derivative acting as a selective Cdk inhibitor, Olomoucine, has been identified from screening against Cdk1/cyclin B complex.5 Olomoucine competitively inhibits Cdk1, Cdk2, Cdk5, and, to a lesser extent, Erk1.5 Recent results have pointed to unexpected pharmacologic properties of 2,6,9trisubstituted purines derived from the Olomoucine lead structure.6,7 To investigate the question in more detail, we developed a program for synthesis and evaluation of new compounds in this series. Twenty-seven derivatives were synthesized and assayed for specific inhibition of Cdk1/cyclin B from starfish oocytes and human recombinant Cdk5/p35 complex. In agreement with earlier results,5 data showed that a strong correlation exists between inhibitory efficiencies against Cdk1 and Cdk5. In contrast, all compounds were only marginally active against Erk1 and Erk2 kinases. One compound in the series, ML-1437, proved much more active than Olomoucine against purified Cdk1/cyclin B, Cdk5/p35, and Cdk2/cyclin E. It also showed pronounced cytotoxicity against human cervix carcinoma HeLa cells in vitro, even on short exposure. Growing IMR-90 (human normal fibroblasts), LoVo (human colon adenocarcinoma), and SQ-20B (human head and neck squamous carcinoma) cells gave similar results, but drug resistance increased rapidly as cells (SQ-20B and IMR-90) reached confluence. These results suggest that the affinity for Cdks and the cytotoxic potential of the drugs are interrelated (FIG. 1, TABLE 1). With the exception of pronounced lengthening of S phase transit during early-S in synchronized HeLa cells, ML-1437 at subtoxic concentration proved unable to produce reversible arrest of the cell cycle progression. When observed, arrest in the G1 and G2 phases of the cell cycle correlated with induced cell death, and chronic exposure to lethal doses of the drug resulted in massive micronucleation in relation to mitotic cell death, with no evidence of endoreduplication (polyploidization) or ap-

  • Synthesis and in vitro evaluation of novel 2,6,9-trisubstituted purines acting as cyclin-dependent kinase inhibitors
    Bioorganic & Medicinal Chemistry, 1999
    Co-Authors: Michel Legraverend, Sophie Leclerc, Laurent Meijer, Odile Ludwig, Emile Bisagni, N. Giocanti, Ramin Sadri, Vincent Favaudon
    Abstract:

    Novel C-2, C-6, N-9 trisubstituted purines derived from the Olomoucine/roscovitine lead structure were synthesized and evaluated for their ability to inhibit starfish oocyte CDK1/cyclin B, neuronal CDK5/p35 and erk1 kinases in purified extracts. Structure-activity relationship studies showed that increased steric bulk at N-9 reduces the inhibitory potential whereas substitution of the aminoethanol C-2 side chain by various groups of diAerent size (methyl, propyl, butyl, phenyl, benzyl) only slightly decreases the activity when compared to (R)-roscovitine. Optimal inhibitory activity against CDK5, CDK1 and CDK2, with IC50 values of 0.16, 0.45 and 0.65mM, respectively, was obtained with compound 21 containing a (2R)-pyrrolidin-2-yl-methanol substituent at the C-2 and a 3-iodobenzylamino group at the C-6 of the purine. Compound 21 proved cytotoxic against human tumor HeLa cells (LD50=6.7mM versus 42.7mM for Olomoucine, 24-h contact). Furthermore, unlike Olomoucine, compound 21 was eAective upon short exposure (LD50=25.3mM, 2-h contact). The available data suggest that the aAnity for CDKs and the cytotoxic potential of the drugs are inter-related. However, no straightforward cell cycle phase specificity of the cytotoxic response to 21 was observed in synchronized HeLa cells. With the noticeable exception of pronounced lengthening of the S-phase transit by 21 applied during early-S in synchronized HeLa cells, and in striking contrast with earlier reports on studies using plant or echinoderm cells, olo- moucine and compound 21 were unable to reversibly arrest cell cycle progression in asynchronous growing HeLa cells. Some irre- versible block in G1 and G2 phase occurred at high Olomoucine concentration, correlated with induced cell death. Moreover, chronic exposure to lethal doses of compound 21 resulted in massive nuclear fragmentation, evocative of mitotic catastrophe with minor amounts of apoptosis only. It was also found that Olomoucine and compound 21 reversibly block the intracellular uptake of nucleosides with high eAciency. # 1999 Elsevier Science Ltd. All rights reserved.

  • the cyclin dependent kinase inhibitors Olomoucine and roscovitine arrest human fibroblasts in g1 phase by specific inhibition of cdk2 kinase activity
    Experimental Cell Research, 1998
    Co-Authors: Francesca Alessi, Laurent Meijer, Santina Quarta, Monica Savio, F Riva, Laura Rossi, Lucia Anna Stivala, Ivana A Scovassi, Ennio Prosperi
    Abstract:

    Abstract The specificity and the temporal location of cell cycle arrest induced by the cyclin-dependent kinase (CDK) inhibitors Olomoucine and roscovitine were investigated in normal human fibroblasts. Effects on the cell cycle were compared with those induced by the kinase inhibitor staurosporine, which arrests normal cells in early G1 phase by acting upstream of CDK2. Consistent with theirin vitroactivity, Olomoucine and roscovitine, but not the related compound iso-Olomoucine, induced a dose-dependent arrest in G1 phase. Following removal of CDK inhibitors, cells resumed cycle progression entering S phase with a kinetics faster than staurosporine-treated samples. Cellular levels of PCNA, cyclin D1, and cyclin E were not affected by the CDK inhibitors. In contrast, staurosporine significantly reduced the levels of these proteins, as determined by immunocytometry and Western blot analysis. Cyclin A was detectable only in some cells remaining in the G2 + M compartment of samples treated with CDK inhibitors, but not in samples treated with staurosporine. Significant reduction in the hyperphosphorylated forms of retinoblastoma protein was found in samples treated with CDK inhibitors, while only hypophosphorylated forms were observed in staurosporine-treated samples. Concomitantly, CDK2, but not CDK4, activity immunoprecipitated from cells treated with Olomoucine or roscovitine was markedly inhibited. These results suggest that in normal cells, CDK2 kinase activity is the specific target of Olomoucine and roscovitine.

Mohamed Abdelrehim - One of the best experts on this subject based on the ideXlab platform.

Wei Wang - One of the best experts on this subject based on the ideXlab platform.

  • effects of cyclin dependent protein kinase inhibitor Olomoucine on the neuronal apoptosis after status epilepticus experiment with rats
    National Medical Journal of China, 2007
    Co-Authors: Xiaoping Du, Zhiyuan Yu, Huaxian Chen, Daishi Tian, Wei Wang
    Abstract:

    Objective To investigate the effects of Olomoucine,a cyclin dependent protein kinase (CDK)inhibitor,on the neuronal apoptosis after status epilepticus(SE).Methods Lithium chloride was injected intraperitoneally,and pilocarpine was injected intraperitoneally after 18 h to 24 SD rats so as to cause SE.Twenty-two of the 24 rats developed SE and 2 of them died.The surviving 20 rats were then randomly divided into 2 equal groups:Olomoucine group,injected intracerebroventricularly after the SE was terminated by diazepam and chloral hydrate once a day for 3 days,and SE group,infused intracerebroventricularly with DMSO solution Another 10 rats were injected intraperitoneally with normal saline and then infused intracerebroventricularly with DMSO solution to be used as control group.Six hours after SE attack 5 rats from each group were killed respectively with their brains taken out.Semiquantitative RT-PCR was used to detect the mRNA expression of anti-inflammatory cytokines,such as interleukin(IL)- 1β and tumor necrosis factor(TNF)-α Three days later the other 5 rats in each group were killed with their entorhinal cortex and hippocampus taken out.TUNEL was used to observe the apoptosis. Immunofluorescence(IF)staining was used to detect the expression of neuronal nuclear nucleoprotein (NeuN)and cyclin B1.Results TUNEL showed that apoptotic neurons were rare in the control group and were numerous in the SE group,especially in the entorhinal cortex and the hylus of dentate gyms,and the number of apoptotic neurons in the hylus of dentate gyrus of the Olomoucine group was not significantly different from that of the control group(P0.05),however,the number of apoptotic cells in the entorhinal cortex of the Olomoucine group was still significantly higher than that of the control group(P0.05).IF staining demonstrated that in the control group the co-expression of NeuN and TUNEL-labeled cells was weak;and in the SE group the co-expression of NeuN and TUNEL was significantly increased compared with that in the control group(P0.05).The number of cyclin B1 positive cells in the Olomoucine group was 18.22±3.99,significantly lower than that of the SE group(24.57±6.78,P0.05).Semiquantitative RT-PCR showed that the IL-1β and TNF-α mRNA expression levels of the SE group were both significantly higher than those of the control group(both P0.05),and the IL-1β and TNF-α mRNA expression levels of the Olomoucine group,except the TNF-α mRNA expression in the cortex,were all significantly lower than those of the SE group(all P0.05),and not significantly different from those of the control group(all P 0.05).Conclusion Olomoueine treatment can inhibits cell cycle protein B1 expression,anti-inflammatory cytokines such as IL-1β and TNF-α secretion,thus decreasing neuronal death and providing neuroprotection after SE,which suggests a potential promising therapeutic way for epilepsy treatment.

  • attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor Olomoucine in rat spinal cord injury model
    Brain Research, 2007
    Co-Authors: Daishi Tian, Zhiyuan Yu, Qiang Dong, Yi He, Wei Wang
    Abstract:

    Abstract Microglial activation/proliferation and reactive astrogliosis are commonly observed and have been considered to be closely relevant pathological processes during spinal cord injury (SCI). However, the molecular mechanisms underlying this microglial–astroglial interaction are still poorly understood. We showed recently that the continuous injection of the cell cycle inhibitor Olomoucine not only markedly suppressed microglial proliferation and associated release of pro-inflammatory cytokines, but also attenuated astroglial scar formation and the lesion cavity and mitigated the functional deficits in rat SCI animal model. In this study, we asked whether microglial activation/proliferation plays an initial role and also necessary in maintaining astrogliosis in SCI model. Our results showed that traumatic induced microglial activation/proliferation precedes astrogliosis, and the up-regulated GFAP expression at both mRNA and protein levels was temporally posterior to the microglial activation. Furthermore, when the cell cycle inhibitor Olomoucine was administered only once 1 h post-SCI that should selectively suppress microglial proliferation, the subsequent SCI induced increase in GFAP expression at 1, 2 and 4 weeks was significantly attenuated, suggesting that microglial activation/proliferation played an important role for the later onset astrogliosis after SCI. Consistent with the results that microglial proliferation always precedes astroglial proliferation and there is at present no evidence of other astroglial precursors, which as always does not mean that they will not be uncovered by further searching, and in view of the fact that microglial-derived pro-inflammatory cytokines promote astrogliosis as we reported recently, these findings together suggest that by release of cytokines and other soluble products, the early onset microglial activation/proliferation can significantly influence the subsequent development of reactive astrogliosis and glial scar formation in SCI animal model.

  • Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo.
    Glia, 2007
    Co-Authors: Qiang Zhang, Zhiyuan Yu, Daishi Tian, Bitao Bu, Liang Zhang, Wei Wang
    Abstract:

    Astrogliosis occurs in a variety of neuropathological disorders and injuries, and excessive astrogliosis can be devastating to the recovery of neuronal function. In this study, we asked whether reactive astrogliosis can be suppressed in the lesion area by cell cycle inhibition and thus have therapeutic benefits. Reactive astrogliosis induced in either cultured astrocytes by hypoxia or scratch injury, or in a middle cerebral artery occlusion (MCAO) ischemia model were combined to address this issue. In the cultured astrocytes, hypoxia induced a cell cycle activation that was associated with upregulation of the proliferating cell nuclear marker (PCNA). Significantly, the cell cycle inhibitor, Olomoucine, inhibited hypoxia-induced cell cycle activation by arresting the cells at G1/S and G2/M in a dose-dependent manner and also reversed hypoxia-induced upregulation of PCNA. Also in the cultured astrocytes, scratch injury induced reactive astrogliosis, such as hypertrophy and an increase in BrdU(+) astrocytes, both of which were ameliorated by Olomoucine. In the MCAO ischemia mouse model, dense reactive glial fibrillary acidic protein and PCNA immunoreactivity were evident at the boundary zone of focal cerebral ischemia at days 7 and 30 after MCAO. We found that intraperitoneal Olomoucine administration significantly inhibited these astrogliosis-associated changes. To demonstrate further that cell cycle regulation impacts on astrogliosis, cyclin D1 gene knockout mice (cyclin D1−/−) were subjected to ischemia, and we found that the percentage of Ki67-positive astrocytes in these mice was markedly reduced in the boundary zone. The number of apoptotic neurons and the lesion volume in cyclin D1−/− mice also decreased as compared to cyclin D1+/+ and cyclin D1+/− mice at days 3, 7, and 30 after local cerebral ischemia. Together, these in vitro and in vivo results strongly suggest that astrogliosis can be significantly affected by cell cycle inhibition, which therefore emerges as a promising intervention to attenuate reactive glia-related damage to neuronal function in brain pathology. © 2007 Wiley-Liss, Inc.

  • Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuronal cell death after spinal cord injury in rats.
    Brain Research, 2006
    Co-Authors: Daishi Tian, Zhiyuan Yu, Qiang Zhang, Yi-hui Wang, Bin Chen, Chen Chen, Wei Wang
    Abstract:

    Abstract The spinal cord is well known to undergo inflammatory reactions in response to traumatic injury. Activation and proliferation of microglial cells, with associated proinflammatory cytokines expression, plays an important role in the secondary damage following spinal cord injury. It is likely that microglial cells are at the center of injury cascade and are targets for treatments of CNS traumatic diseases. Recently, we have demonstrated that the cell cycle inhibitor Olomoucine attenuates astroglial proliferation and glial scar formation, decreases lesion cavity and mitigates functional deficits after spinal cord injury (SCI) in rats [Tian, D.S., Yu, Z.Y., Xie, M.J., Bu, B.T., Witte, O.W., Wang, W., 2006. Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor Olomoucine. J. Neurosci. Res. 84, 1053–1063]. Whether neuroprotective effects of cell cycle inhibition are involved in attenuation of microglial induced inflammation awaits to be elucidated. In the present study, we sought to determine the influence of Olomoucine on microglial proliferation with associated inflammatory response after spinal cord injury. Tissue edema formation, microglial response and neuronal cell death were quantified in rats subjected to spinal cord hemisection. Microglial proliferation and neuronal apoptosis were observed by immunofluorescence. Level of the proinflammatory cytokine interleukin-1β (IL-1β) expression in the injured cord was determined by Western blot analysis. Our results showed that the cell cycle inhibitor Olomoucine, administered at 1 h post injury, significantly suppressed microglial proliferation and produced a remarkable reduction of tissue edema formation. In the Olomoucine-treated group, a significant reduction of activated and/or proliferated microglial induced IL-1β expression was observed 24 h after SCI. Moreover, Olomoucine evidently attenuated the number of apoptotic neurons after SCI. Our findings suggest that modulation of microglial proliferation with associated proinflammatory cytokine expression may be a mechanism of cell cycle inhibition-mediated neuroprotections in the CNS trauma.

  • suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor Olomoucine
    Journal of Neuroscience Research, 2006
    Co-Authors: Daishi Tian, Zhiyuan Yu, Bitao Bu, Otto W Witte, Wei Wang
    Abstract:

    It is well established that axons of the adult mammalian CNS are capable of regrowing only a limited amount after injury. Astrocytes are believed to play a crucial role in the failure to regenerate, producing multiple inhibitory proteoglycans, such as chondroitin sulphate proteoglycans (CSPGs). After spinal cord injury (SCI), astrocytes become hypertrophic and proliferative and form a dense network of astroglial processes at the site of lesion constituting a physical and biochemical barrier. Down-regulations of astroglial proliferation and inhibitory CSPG production might facilitate axonal regeneration. Recent reports indicated that aberrant activation of cell cycle machinery contributed to overproliferation and apoptosis of cells in various insults. In the present study, we sought to determine whether a cell cycle inhibitior, Olomoucine, would decrease neuronal cell death, limit astroglial proliferation and production of inhibitory CSPGs, and eventually enhance the functional compensation after SCI in rats. Our results showed that up-regulations of cell cycle components were closely associated with neuronal cell death and astroglial proliferation as well as the production of CSPGs after SCI. Meanwhile, administration of Olomoucine, a selective cell cycle kinase (CDK) inhibitor, has remarkably reduced the up-regulated cell cycle proteins and then decreased neuronal cell death, astroglial proliferation, and accumulation of CSPGs. More importantly, the treatment with Olomoucine has also increased expression of growth-associated proteins-43, reduced cavity formation, and improved functional deficits. We consider that suppressing astroglial cell cycle in acute SCIs is beneficial to axonal growth. In the future, therapeutic strategies can be designed to achieve efficient axonal regeneration and functional compensation after traumatic CNS injury. © 2006 Wiley-Liss, Inc.

Moustapha Hassan - One of the best experts on this subject based on the ideXlab platform.

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