Article (Scientific journals)
beta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway
Hans, Grégory; Malgrange, Brigitte; Lallemend, François et al.
2005In Neuropharmacology, 48 (1), p. 105-117
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Keywords :
apoptosis; mitochondrion; caspases; beta-carbolines; cerebellar granule neurons
Abstract :
[en] N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities with the synthetic neurotoxin 1-methy14-phenyl-1,2,3,6-tetrahydropyridine (MPTP), harman and norharman compounds have been proposed to be involved in the pathogenesis of Parkinson's disease. While also structurally related, betaCCB has received much less interest in that respect although we had previously demonstrated that it induces the apoptotic cell death of cultured cerebellar granule neurons (CGNs). Herein, we have investigated the molecular events leading to CGN apoptosis upon betaCCB treatment. We first demonstrated that betaCCB-induced apoptosis occurs in neurons only, most likely as a consequence of a specific neuronal uptake as shown using binding/uptake experiments. Then we observed that, in betaCCB-treated CGNs, caspases 9, 3 and 8 were successively activated, suegesing an activation of the mitochondrial pathway. Consistently, betaCCB also induced the release from the mitochondrial intermembrane space of two pro-apoptotic factors. i.e. cytochrome c and apotptosis inducing factor (AIF). Interestingly, no mitochondrial membrane depolarisation was associated with this release. suggesting a mitochondrial permeability transition pore-independent mechanism. The absence of any neuroprotective effect provided by two mPTP inhibitors. i.e. cyclosporine A and bongkrekic acid. further supported this hypothesis. Together. these results show that betaCCB is specifically taken up by neuronal cells where it triggers a specific permeabilization of the outer mitochondrial membrane and a subsequent apoptotic cell death. (C) 2004 Elsevier Ltd. All rights reserved.
Disciplines :
Neurosciences & behavior
Pharmacy, pharmacology & toxicology
Author, co-author :
Hans, Grégory ;  Centre Hospitalier Universitaire de Liège - CHU > Anesthésie et réanimation
Malgrange, Brigitte  ;  Université de Liège - ULiège > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc.
Lallemend, François
Crommen, Jacques ;  Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Wislet-Gendebien, Sabine  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
Belachew, Shibeshih ;  Université de Liège - ULiège > Département des sciences cliniques > Neurologie
Robe, Pierre ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Rogister, Bernard  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
Moonen, Gustave  ;  Université de Liège - ULiège > Département des sciences cliniques > Neurologie - Doyen de la Faculté de Médecine
Rigo, Jean-Michel;  Universiteit Hasselt - UH
Language :
English
Title :
beta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway
Publication date :
January 2005
Journal title :
Neuropharmacology
ISSN :
0028-3908
eISSN :
1873-7064
Publisher :
Pergamon-Elsevier Science Ltd, Oxford, United Kingdom
Volume :
48
Issue :
1
Pages :
105-117
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Available on ORBi :
since 26 January 2009

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