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Brand: celine bag leather, Early raise of BDNF in hippocampus suggests induction of posttranscriptional mechanisms AbstractBackgroundThe neurotrophin BDNF has been implicated in the regulation of neuroplasticity, gene expression, and synaptic function in the adult brain, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. Antidepressant treatments have been shown to increase the expression of BDNF mRNA, although the changes measured were found to be different depending on various factors. A few studies only have measured levels of BDNF protein after antidepressant treatments, and poor correlation was found between mRNA and protein changes. We studied the time course of expression of BDNF mRNA and protein during drug treatments, in order to elucidate the temporal profile of regulation of this effector and whether mRNA and protein levels correlate. Rat groups were treated for 1, 2 or 3 weeks with fluoxetine or reboxetine; in additional groups drug treatment was followed by a washout week (3+1). Total BDNF mRNA was measured by Real Time PCR, pro and mature BDNF proteins were measured by Western blot.ResultsWe found that mature BDNF protein is induced more rapidly than mRNA, by both drugs in hippocampus (weeks 1 and by reboxetine in prefrontal/frontal cortex (week 1). The temporal profile of BDNF protein expression was largely inconsistent with that of mRNA, which followed the protein induction and reached a peak at week 3.ConclusionThese results suggest that BDNF protein is rapidly elevated by antidepressant treatments by posttranscriptional mechanisms, and that induction of BDNF mRNA is a slower process.BackgroundBrain Derived Neurotrophic Factor (BDNF) is an abundant neurotrophin regulating neuroplasticity, gene expression, synaptic function and cognition in the adult brain [1,2], that has been implicated in the pathophysiology of various neuropsychiatric and neurodegenerative disorders as well as in the mechanism of action of antidepressant drugs [3 9]. It is generally assumed that antidepressant treatments increase the expression of BDNF, which, according to the neurotrophic hypothesis, represents an effector of changes in neuroplasticity and cellular resilience mediating the long term therapeutic effect of antidepressants. In this framework BDNF has lately become, together with the activation of cAMP response element binding protein (CREB), a sort of readout system in the study of antidepressant mechanisms [4,5,7,8,10 14].However, several studies have shown that the changes in the expression of BDNF can be quite different depending on various factors, such as type of drug, dosage, route of administration, length of treatment (see ref. [9] for discussion). Moreover, only a few studies have measured levels of BDNF protein after antidepressant treatments [10,15 19] and, when mRNA and protein levels have been measured at the same time, poor correlation was found between mRNA and protein changes [16,17]. In addition, the rat BDNF gene has a complex structure with at least eight 5' exons that can be spliced to a single 3' exon containing the coding domain for the BDNF protein, generating 11 different hermes staff transcripts according to the last nomenclature [20]. This makes the effect of drug treatments on BDNF expression more complex to explain, because the changes hermes kelly bag in total BDNF can potentially be related to changes in different non coding exons spliced to the coding exon (exon IX).In this study, with regard to the action of antidepressants, we asked the following questions:1. What is the time course of BDNF expression during antidepressant treatment? Is it consistent with the onset of therapeutic effect?2. What is the expression level of BDNF after1 week washout?3. How does BDNF protein expression profile during treatment correlate with BDNF mRNA expression?In order to assess the time course of BDNF expression during long term antidepressant treatments, we have treated rats with two different drugs endowed with complementary mechanisms: fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), and reboxetine (RBX), a selective norepinephrine reuptake inhibitor (NRI). The drug treatments were carried out for 1, 2 or 3 weeks and were followed by an additional washout week (3+1), that was added in order to study the fate celine purses of BDNF expression when antidepressant treatment is discontinued. In all these rat groups we assessed the expression of total BDNF at Celine sale Boston both mRNA and protein levels, measuring both the pro and mature forms of BDNF [1,21,22]. We found that mature BDNF protein is induced in hippocampus more rapidly than mRNA, suggesting that antidepressants rapidly regulate BDNF at posttranscriptional level.ResultsDistinct temporal profile of expression of total BDNF mRNA induced by fluoxetine and reboxetineWe measured the changes in BDNF expression induced by the two drug treatments at the level of both mRNA and protein, in HPC and P/FC. Total BDNF mRNA was detected by means of quantitative Real Time PCR, using primers designed on the sequence of the coding exon (exon IX). 2 Way ANOVA showed in HPC an effect of time (F4,79 = 147.31; p 0.0001), drug (F1,79 = 37.31; p 0.0001) and time/drug interaction (F4,79 = 24.61; p 0.0001). Similarly, in P/FC there was an effect of time (F4,50 = 44.24; p 0.0001), drug (F1,50 = 4.38; p 0.0001) and time drug interaction (F4,50 = 3.80; p 0.01). As shown in Fig. 1A the temporal profile of activation of mRNA expression by FLX and RBX was similar in the two brain areas, but typical of either drug. The jrrenterprises.com levels of total BDNF mRNA were induced starting with week 1 (RBX) or 2 (FLX) and peaked at week 3 with both drugs (particularly with FLX). During the washout week the mRNA level was sharply reduced for FLX, although maintaining a significantly higher than basal level. This gap between week 3 and 3+1 was less pronounced for RBX, for which the mRNA level at week 3+1 was also significantly higher than basal level.Figure 1Time course of expression levels of BDNF total mRNA following antidepressant treatment. Expression levels of BDNF total mRNA in HPC (A) and P/FC (B) of rats treated with FLX and RBX. Bonferroni.Expression profile of BDNF protein induced by fluoxetine and reboxetine consistent with early translation of mRNAThe expression of the BDNF protein follows a multi step process of maturation from a pre propeptide through a proprotein to the mature form of BDNF [21]. We measured by Western blot both the 32 kDa pro BDNF and 14 kDa mature BDNF, the two most abundant forms of the protein [1,5], in the total extract of HPC and P/FC at the different treatment times as above (Fig. The two drugs showed different effects on BDNF protein levels in the two areas. In HPC (Fig. 2A 2 Way ANOVA showed an effect of time and drug for both pro BDNF (F4,59 = 26.71; p 0.0001; F1,59 = 24.16; p 0.0001) and mature BDNF (F4,89 = 12.17; p 0.0001; F1,89 = 65.08; p 0.0001) and of time/drug interaction for pro BDNF (F4,59 = 4.65; p 0.01). In HPC, FLX induced a trend toward increase of pro BDNF at weeks 1 which became significant at week 3, while RBX hermes symbol up regulated pro BDNF at weeks 2 Both FLX and RBX consistently up regulated the expression of mature BDNF at all times in HPC, with maximum at weeks 2 for FLX and 1 to 3 for RBX (Fig. 2A ft0 >Figure 2Time course of expression levels of BDNF protein following antidepressant treatment. Time course of expression levels of BDNF protein precursor of 32 kDa (A, B) and mature protein celine trapeze of 14 kDa (C, D) in HPC (A, C) and P/FC (B, D) of rats treated with FLX.In P/FC (Fig. 2B 2 Way ANOVA showed an effect of time (F4,53 = 7.69; p 0.0001) and time/drug interaction (F4,53 = 4.07; p 0.01) for pro BDNF and an effect of time (F4,54 = 44.79; p 0.0001) and drug (F1,54 = 12.53; p 0.001) for mature BDNF. Indeed, both FLX and RBX up regulated pro BDNF, with the only exception of week 3 for FLX. Differently from the HPC, in P/FC the up regulation of pro BDNF by FLX sharply contrasted with the absence of changes in mature BDNF (Fig. 2B As in HPC, RBX consistently up regulated mature BDNF at all times.Overall, the regulation of mRNA and protein was not consistent in HPC and P/FC for both drugs. No mature BDNF was induced by FLX in P/FC. The results showed that in HPC the level of mature BDNF protein reached a peak (weeks 1 before the actual peak of mRNA (week 3), suggesting early translation and processing of the protein during antidepressant treatment. The same was observed for RBX in P/FC. celine bag leather Almost all people An important fast growing tendency The manner in which may How will i celine bag leather Unquestionably are these kind of Frequently Are going to I personally |
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