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Ultrastructural identification of oligodendrocyte/myelin proteins in corpus callosum of hypothyroid animals 总被引:1,自引:0,他引:1
A.A. Ferreira M.J.S. Pereira A.C. Manhes P.C. Barradas 《International journal of developmental neuroscience》2007,25(2):87-94
Thyroid hormone (T3) deficiency impairs the development of the CNS, particularly myelination. We have previously described an increase in the frequency of morphological abnormalities in the central myelin sheath in a hypothyroidism model, which reinforced the hypothesis of a role for T3 in myelin compaction. However, there are no data concerning the cellular distribution of myelin proteins in hypothyroid animals. In the present work, we describe the distribution of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), myelin basic protein (MBP) and proteolipid protein (PLP) throughout the central myelin sheath of a hypothyroidism model. We used euthyroid and hypothyroid adult rats at 90 days of age. In order to induce hypothyroid status, animals received 0.02% methimazol from the 19th gestation day onwards. After perfusion with a fixative mixture, small pieces of corpus callosum were obtained, dehydrated and embedded in LR White resin. Ultrathin sections were immunoreacted, using specific antibodies revealed by a secondary antibody coupled to colloidal gold particles of 10 nm. Gold particle density per region of myelin sheath for each one of these proteins was obtained. In normal animals, CNPase, PLP and MBP were identified in sites that had already been described in previous studies. In hypothyroid animals, CNPase was identified in the region corresponding to compact lamellae, which normally does not contain this protein, while, in this same region, PLP and MBP immunolabeling were decreased. These results suggest that thyroid hormone deficiency impairs the distribution of the major oligodendrocyte/myelin markers. This effect may justify the reduction in myelin sheath compaction previously demonstrated in a similar model of hypothyroidism. 相似文献
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Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling 总被引:35,自引:2,他引:35 下载免费PDF全文
Athena W. Lin Marta Barradas James C. Stone Linda van Aelst Manuel Serrano Scott W. Lowe 《Genes & development》1998,12(19):3008-3019
Oncogenic Ras transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Ras is initially mitogenic but eventually induces premature senescence involving the p53 and p16INK4a tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a. The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Ras mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors. 相似文献
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M. A. Barradas J. Y. Jeremy D. P. Mikhailidis P. Dandona D. Phil F.R.C.P. 《Inflammation research》1989,26(3-4):386-390
The present study compares the effects of two non-steroidal anti-inflammatory drugs (NSAIDs) on platelet function. Tiaprofenic acid (300 mg twice daily) and indomethacin (25 mg thrice daily) were administered to healthy volunteers for 6 days. Platelet aggregation and thromboxane A2 (TXA2) release (assessed as TXB2, the stable, spontaneous breakdown product of TXA2) were assessed before the adminstration of NSAIDs; on day 6 (2–3 h after the last dose of NSAID); and on days 7 and 8 (24 h and 48 h after the last dose of NSAID). Both tiaprofenic acid and indomethacin significantly inhibited platelet aggregation and TXA2 release. The extent and duration of inhibition was similar for both drugs, and the inhibition tended to reverse within 24–48 h of cessation of medication. The time required for reversal of the inhbitiory effect of NSAIDs on platelets may be of relevance in patients who are bleeding (e.g. from gastric erosions caused by NSAIDs). Tiaprofenic acid in the present study and in previous work has not been shown to be a selective inhibitor of prostanoid synthesis, as was originally claimed. 相似文献
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Thyroid hormones are critical for maturation of the central nervous system. In a previous study, we showed a change in the pattern of mature myelinated nerve fibers by 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in developing hypothyroid animals, which suggests a possible role for thyroid hormones in myelin compaction. The classical myelin markers myelin basic protein (MBP) and proteolipidic protein (PLP) are expressed later in oligodendroglial development, when myelin sheath formation is in progress. A myelin constituent designated myelin-associated/oligodendrocytic basic protein (MOBP) has been identified and related to myelin compaction. We assessed the developmental sequence of appearance of CNPase, MBP, MOPB, and PLP proteins in cerebellum (Cb) and corpus callosum (cc) in an experimental hypothyroidism model. The appearance of both MOBP isoforms occurred at postnatal day (P)25 and P30 in cc and Cb, respectively, followed by an increase with age in the control group. However, all the MOBP isoforms were weakly detectable in both regions at P30 from the hypothyroid (H) group, and the higher molecular weight isoform remains decreased in cc, even at P90. The developmental pattern of expression of CNPase, MBP, and PLP proteins was also delayed in the H group. CNPase and MBP expression was recovered in cc and Cb, whereas PLP remained below control levels at P90 in cc. Our data show that the experimental hypothyroidism affects the developmental pattern of the oligodendrocytic/myelin markers. Furthermore, thyroid hormone may modulate specific genes, as demonstrated by permanent down-regulation of MOBP and PLP expression in adulthood. 相似文献
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V. Younes-Rapozo L.O.R. Felgueiras N.L. Viana I.M. Fierro C. Barja-Fidalgo A.C. Manhães P.C. Barradas 《International journal of developmental neuroscience》2009
The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is important for both long-term survival and timing of the progression of oligodendrocyte differentiation. Oligodendroglial cells treated with MEK inhibitor were distinguished by using stage specific markers: NG2 proteoglycan, A2B5, 2′3′nucleotide-cyclic 3′phosphodiesterase (CNPase) and myelin basic protein (MBP), and classified according to their morphology into different developmental stages. Treatment significantly increased the number of cells with more immature morphologies and decreased the number of mature cells. Furthermore, it increased the number of rounded cells that could not be classified into any of the oligodendroglial developmental stages. The strongest effects were usually observed shortly after treatment. Rounded cells were CNPase/MBP positive and they were not stained by anti-NG2 or A2B5, indicating that they were mature cells unable either to extend and/or to maintain their processes. These data showed an effect of the MAPK/ERK pathway on oligodendroglial branching, with possible consequences for the formation of the myelin sheath. 相似文献