title: Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Trophos, Marseille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Gouarné
authors.forename: Marc
authors.initials: M
authors.lastname: Giraudon-Paoli
authors.forename: Mathieu
authors.initials: M
authors.lastname: Seimandi
authors.forename: Clotilde
authors.initials: C
authors.lastname: Biscarrat
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Tardif
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
authors.forename: Thierry
authors.initials: T
authors.lastname: Bordet
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology*; D002783:Cholestenones / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008928:Mitochondria / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D002783:Cholestenones; D009570:Nitriles; D016159:Tumor Suppressor Protein p53; C113580:U 0126; C522838:olesoxime; D002166:Camptothecin