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

摘要: 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 glyceraldehyde-3-phosphate dehydrogenase (GAPDH) animal model with motoneuron degeneration, i.e. a mouse mutant progressive motor neuronopathy (pmn). In pmn/pmn mice, CGP 3466B was administered (10–100 nmol kg−1) at onset clinical symptoms (2 weeks after birth). slowed disease progression as determined by 57% increase life-span, preservation body weight performance. This improvement accompanied decreased loss motoneurons fibres well retrograde transport. Electron microscopic analysis showed protects mitochondria which appear selectively disrupted mice. The data support evaluation potential treatment for neuron disease. Keywords: Apoptosis, disease, pmn non-peptidic molecule, mitochondria, 3466B, GAPDH Introduction Motor is general term groups various diseases common manifestation, death spinal cord, brain stem cortex. Amyotrophic lateral sclerosis (ALS) muscular atrophy (SMA) most frequent forms very poor prognosis. Neurotrophic factors been considered possible these because their ability act on neuronal survival prevent apoptosis injury paradigms. However has so far disappointing probably inability cross blood barrier (BBB) (for reviews see Rothstein, 1996; Morrison & Morrison, 1999). A new surge studies suggested small molecules ‘trophic' activity not only BBB but also bioavailable. One riluzole originally shown inhibit glutamate release CNS subsequently rescue familial amyotrophic (FALS) (Gurney et al., 1996). Riluzole now used standard therapy ALS (Wokke, Other organic such CEP-1347 promote vitro vivo (Maroney 1998; Glicksman 1998). SR57746A, another nonpeptide compound, improves function (progressive neuronopathy) following oral (Duong 1998). Here we report delivered neuroprotective agent (pmn) spontaneous recessive mutation resulting fibres. structurally related both classical tricyclic antidepressent agents monoamine oxidase inhibitors lacks pharmacological properties relevant anti-depressant effects (Kragten It human neuroblastoma PC-12 cells from apoptotic Carlile 2000) cerebellar granule induced cytosine arabinoside (Paterson 1998a), hippocampal pyramidal ischaemic kainate-induced cell 1998b). In several parameters disease. prevents disruption, stimulates axonal transport concomitantly slows down degeneration. These lead life-span animals weight.