title: An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease.
abstract: Apoptosis and mitochondrial dysfunction are thought to be involved in the aetiology of neurodegenerative diseases. We have tested an orally active anti-apoptotic molecule (CGP 3466B) that binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in an animal model with motoneuron degeneration, i.e. a mouse mutant with progressive motor neuronopathy (pmn). In pmn/pmn mice, CGP 3466B was administered orally (10 - 100 nmol kg(-1)) at the onset of the clinical symptoms (2 weeks after birth). CGP 3466B slowed disease progression as determined by a 57% increase in life-span, preservation of body weight and motor performance. This improvement was accompanied by a decreased loss of motoneurons and motoneuron fibres as well as an increase in retrograde transport. Electron microscopic analysis showed that CGP 3466B protects mitochondria which appear to be selectively disrupted in the motoneurons of pmn/pmn mice. The data support evaluation of CGP 3466B as a potential treatment for motor neuron disease.
authors.affiliation: Department of APSIC and Division of Clinical Neuromuscular Research, Faculty of Medicine, Geneva University, 1211 Geneva 4, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Sagot
authors.forename: N
authors.initials: N
authors.lastname: Toni
authors.forename: D
authors.initials: D
authors.lastname: Perrelet
authors.forename: S
authors.initials: S
authors.lastname: Lurot
authors.forename: B
authors.initials: B
authors.lastname: King
authors.forename: H
authors.initials: H
authors.lastname: Rixner
authors.forename: L
authors.initials: L
authors.lastname: Mattenberger
authors.forename: P C
authors.initials: PC
authors.lastname: Waldmeier
authors.forename: A C
authors.initials: AC
authors.lastname: Kato
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000401:mortality; D009046:Motor Neurons / Q000187:drug effects; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D010082:Oxepins / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010082:Oxepins; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases