PMID- 23278424
OWN - NLM
STAT- MEDLINE
DCOM- 20150713
LR  - 20211021
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 168
IP  - 8
DP  - 2013 Apr
TI  - Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a 
      mechanism distinct from BDNF.
PG  - 1975-88
LID - 10.1111/bph.12094 [doi]
AB  - 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.
CI  - (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British 
      Pharmacological Society.
FAU - Gouarne, Caroline
AU  - Gouarne C
AD  - Trophos, Marseille, France.
FAU - Giraudon-Paoli, Marc
AU  - Giraudon-Paoli M
FAU - Seimandi, Mathieu
AU  - Seimandi M
FAU - Biscarrat, Clotilde
AU  - Biscarrat C
FAU - Tardif, Gwenaelle
AU  - Tardif G
FAU - Pruss, Rebecca M
AU  - Pruss RM
FAU - Bordet, Thierry
AU  - Bordet T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Butadienes)
RN  - 0 (Cholestenones)
RN  - 0 (Nitriles)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (U 0126)
RN  - A6778U5IFY (olesoxime)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Butadienes/pharmacology
MH  - Camptothecin/pharmacology/*toxicity
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/*embryology
MH  - Cholestenones/administration & dosage/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Embryo, Mammalian/cytology
MH  - Female
MH  - Gene Expression Regulation
MH  - MAP Kinase Signaling System/*drug effects
MH  - Mitochondria/physiology
MH  - Neurons/*drug effects
MH  - Nitriles/pharmacology
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tumor Suppressor Protein p53/metabolism
PMC - PMC3623066
EDAT- 2013/01/03 06:00
MHDA- 2015/07/15 06:00
PMCR- 2014/04/01
CRDT- 2013/01/03 06:00
PHST- 2012/08/29 00:00 [received]
PHST- 2012/11/28 00:00 [revised]
PHST- 2012/12/10 00:00 [accepted]
PHST- 2013/01/03 06:00 [entrez]
PHST- 2013/01/03 06:00 [pubmed]
PHST- 2015/07/15 06:00 [medline]
PHST- 2014/04/01 00:00 [pmc-release]
AID - 10.1111/bph.12094 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2013 Apr;168(8):1975-88. doi: 10.1111/bph.12094.