Dataset Information

Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF.

ABSTRACT:

Background and purpose

Olesoxime is a small cholesterol-oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain-derived neurotrophic factor (BDNF).

Experimental approach

E17 rat embryonic cortical neurons were treated with olesoxime, BDNF or vehicle and intoxicated with CPT. Caspase-dependent and caspase-independent death pathways along with pro-survival pathways activation were explored.

Key results

As previously reported for BDNF, olesoxime dose-dependently delayed CPT-induced cell death. Both compounds acted downstream of p53 activation preventing cytochrome c release and caspases activation. When caspase activation was blocked, both olesoxime and BDNF provided additional neuroprotective effect, potentially through the prevention of apoptosis-inducing factor release from mitochondria. While BDNF activates both the PI3K/Akt and the ERK pathway, olesoxime induced only a late activation of the ERK pathways, which did not seem to play a major role in its neuroprotection against CPT. Rather, our results favour preserved mitochondrial membrane integrity by olesoxime.

Conclusions and implications

Albeit different, olesoxime and BDNF mechanisms for neuroprotection converge to preserve mitochondrial function. These findings emphasize the importance of targeting the mitochondria in the process of neurodegeneration. Importantly olesoxime, by mimicking neurotrophin pro-survival activities without impacting PI3K/Akt and ERK signalling, may have greater therapeutic potential in many diseases where neurotrophins were considered as a therapeutic solution.

SUBMITTER: Gouarne C

PROVIDER: S-EPMC3623066 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Publications

Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF.

Gouarné Caroline C Giraudon-Paoli Marc M Seimandi Mathieu M Biscarrat Clotilde C Tardif Gwenaëlle G Pruss Rebecca M RM Bordet Thierry T

British journal of pharmacology 20130401 8

<h4>Background and purpose</h4>Olesoxime is a small cholesterol-oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain-derived neurotrophic factor (BDNF).<h4>Experimental approach</h4>E17 rat embryonic cor ...[more]

PMID: 23278424

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Project description:Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin that supports the survival, differentiation, and signaling of various neuronal populations. Although it has been well described that expression of BDNF is strongly regulated by neuronal activity, little is known whether regulation of BDNF expression is similar in different brain regions. Here, we focused on this fundamental question using neuronal populations obtained from rat cerebral cortices and hippocampi of both sexes. First, we thoroughly characterized the role of the best-described regulators of BDNF gene - cAMP response element binding protein (CREB) family transcription factors, and show that activity-dependent BDNF expression depends more on CREB and the coactivators CREB binding protein (CBP) and CREB-regulated transcriptional coactivator 1 (CRTC1) in cortical than in hippocampal neurons. Our data also reveal an important role of CREB in the early induction of BDNF mRNA expression after neuronal activity and only modest contribution after prolonged neuronal activity. We further corroborated our findings at BDNF protein level. To determine the transcription factors regulating BDNF expression in these rat brain regions in addition to CREB family, we used in vitro DNA pulldown assay coupled with mass spectrometry, chromatin immunoprecipitation (ChIP), and bioinformatics, and propose a number of neurodevelopmentally important transcription factors, such as FOXP1, SATB2, RAI1, BCL11A, and TCF4 as brain region-specific regulators of BDNF expression. Together, our data reveal complicated brain region-specific fine-tuning of BDNF expression.SIGNIFICANCE STATEMENT To date, majority of the research has focused on the regulation of brain-derived neurotrophic factor (BDNF) in the brain but much less is known whether the regulation of BDNF expression is universal in different brain regions and neuronal populations. Here, we report that the best described regulators of BDNF gene from the cAMP-response element binding protein (CREB) transcription factor family have a more profound role in the activity-dependent regulation of BDNF in cortex than in hippocampus. Our results indicate a brain region-specific fine tuning of BDNF expression. Moreover, we have used unbiased determination of novel regulators of the BDNF gene and report a number of neurodevelopmentally important transcription factors as novel potential regulators of the BDNF expression.

Dataset Information

Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF.

Similar Datasets

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