An orally active anti‐apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease

• Published in: British journal of pharmacology Vol. 131; no. 4; pp. 721 - 728
• Main Authors: Sagot, Y, Toni, N, Perrelet, D, Lurot, S, King, B, Rixner, H, Mattenberger, L, Waldmeier, P C, Kato, A C
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2000; Nature Publishing
• Subjects: Administration, Oral; Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; CGP 3466B; Disease Models, Animal; GAPDH; Glial Cell Line-Derived Neurotrophic Factor; Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; Medical sciences; Mice; mitochondria; Mitochondria - drug effects; motoneuron disease; Motor Neuron Disease - drug therapy; Motor Neuron Disease - mortality; Motor Neurons - drug effects; Nerve Growth Factors; Nerve Tissue Proteins - pharmacology; Neuropharmacology; Neuroprotective agent; non‐peptidic molecule; Oxepins - pharmacology; Pharmacology. Drug treatments; pmn mice; Weight Loss - drug effects; Nervous system diseases; Treatment efficiency; Rodentia; Motor neuron disease; Oral administration; Neuroprotective agent; Biological activity; Vertebrata; Chemotherapy; Mitochondria; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; Degenerative disease; Intracellular; Mechanism of action; Spinal cord disease; Apoptosis
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703633

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. British Journal of Pharmacology (2000) 131, 721–728; doi:10.1038/sj.bjp.0703633