Effetti protettivi del 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclo-propanecarboxylic Acid (CHF5074) su cellule neuronali sottoposte a stimoli tossici in vitro.
Protective effects of 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic Acid(CHF5074) on neural cells challenged with toxic stimuli in vitro. Nicole Ronsisvalle, Renato Bernadini,Rosa Chillemi Dept of Clinical and Molecular Biomedicine, section on Pharmacology and Biochemistry, Univ of Catania Sch Med, 95125 Catania, Italy Alzheimer¡¦s disease (AD) is the most common form of dementia. The basic pathological abnormalities in AD brains are: amyloid plaques, neurofibrillary tangles and neuronal loss. Amyloid plaques are composed of £]-amyloid (A£]) peptides that are proteolytically produced from the amyloid precurson protein (APP). APP is initially cleaved by £^-secretase to generate a 99-residue carboxy-terminal fragment that is subsequently cleaved by £^-secretase to generate A£]. 1-(3 S,4 S-Dichloro-2-fluoro[1,1 S-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074) has been regarded as a modulator of £^-secretase. Thus, we evaluated the effects of CHF5074 on A£] related TRAIL toxicity in the human neuronal cell line SH-SY5Y, as well as in primary cultures of rat embryo cortical and hippocampal neurons cultured in vitro. All cells were treated 1h with CHF5074 at graded concentrations (range: 1-100 nM) and incubated for 72 h with A£] or TRAIL. Results show that CHF5074 prevented apoptotic death in all the cell types tested in a concentration-dependent fashion. The maximally active concentration was 10nM. In addition, we explored molecular mechanisms underlying the protective effect of the drug. Preliminary data suggest that either Caspases, as well as Stress and MAP kinases are among molecular mechanisms affected by the mode of action of CHF5074. Finally, treatment with CHF5074 has shown that the drug protects neural cells from apoptotic death. Therefore, it could be envisioned that CHF5074 represents a candidate potential therapeutic tool in AD.
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