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Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF
Caroline Gouarné1, Marc Giraudon-Paoli, Mathieu Seimandi
1Trophos, Marseille, France.
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.
Insights
Olesoxime protects rat neurons from death by preserving mitochondrial integrity, similar to brain-derived neurotrophic factor (BDNF) but via a distinct mechanism. This highlights mitochondria as a key target for neuroprotection strategies.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Olesoxime, a cholesterol-oxime, promotes motor neuron survival.
- Its mechanism of action and neuroprotective potential warrant further investigation.
Purpose of the Study:
- To investigate olesoxime's neuroprotective effects against camptothecin (CPT)-induced neuronal death.
- To compare olesoxime's mechanism with that of brain-derived neurotrophic factor (BDNF).
Main Methods:
- E17 rat cortical neurons were treated with olesoxime or BDNF and exposed to CPT.
- Caspase-dependent and -independent cell death pathways were analyzed.
- Pro-survival signaling pathways were explored.
Main Results:
- Olesoxime, like BDNF, dose-dependently delayed CPT-induced cell death.
- Both compounds prevented cell death downstream of p53 activation.
- Olesoxime preserved mitochondrial membrane integrity, a key neuroprotective mechanism.
Conclusions:
- Olesoxime and BDNF share the common goal of preserving mitochondrial function for neuroprotection, despite differing molecular pathways.
- Olesoxime's distinct mechanism, bypassing PI3K/Akt and ERK signaling, suggests significant therapeutic potential for neurodegenerative diseases.