Protective effects of compound FLZ, a novel synthetic analogue of squamosamide, on beta-amyloid-induced rat brain mitochondrial dysfunction in vitro.
OBJECTIVE
The aim of the present study was to assess the effects of N-[2-(4-hydroxyphenyl)ethyl]-2-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxyphenyl) acrylamide (compound FLZ), a novel synthetic analogue of squamosamide, on the dysfunction of rat brain mitochondria induced by Abeta(25-35) in vitro.


METHODS
Isolated rat brain mitochondria were incubated with aged Abeta(25-35) for 30 min in the presence and absence of FLZ (1-100 micromol/L). The activities of key mitochondrial enzymes, the production of hydrogen peroxide (H(2)O(2)) and superoxide anion (O2*-), and the levels of glutathione (GSH) in mitochondria were examined. Mitochondrial swelling and the release of cytochrome c from mitochondria were assessed by biochemical and Western blot methods, respectively.


RESULTS
Incubation of mitochondria with aged Abeta(25-35) inhibited the activities of alpha-ketoglutarate dehydrogenase (alpha-KGDH), pyruvate dehydrogenase (PDH) and respiratory chain complex IV. It also resulted in increased H(2)O(2) and (O2*-) production, and decreased the GSH level in mitochondria. Furthermore, it induced mitochondrial swelling and cytochrome c release from the mitochondria. The addition of FLZ (100 micromol/L) prior to treatment with Abeta(25-35) significantly prevented these toxic effects of Abeta(25-35) on the mitochondria.


CONCLUSIONS
FLZ has a protective effect against Abeta(25-35)-induced mitochondrial dysfunction in vitro.
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Fang
F
Fang
Geng-tao
GT
Liu
D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010446:Peptide Fragments / Q000009:adverse effects*; D010636:Phenols / Q000494:pharmacology*; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D044482:Benzeneacetamides; D010446:Peptide Fragments; D010636:Phenols; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); C084439:squamosamide; D045304:Cytochromes c; D030481:Pyruvate Dehydrogenase (Lipoamide); D007655:Ketoglutarate Dehydrogenase Complex; D005978:Glutathione