Mango D, Barbato G, Piccirilli S, Panico M B, Feligioni M, Schepisi C, Graziani M, Porrini V, Benarese M, Lanzillotta A, Pizzi M, Pieraccini S, Sironi M, Blandini F, Nicoletti F, Mercuri N B, Imbimbo B P, Nisticò R
IRCCS Santa Lucia Foundation, Rome, Italy.
European Brain Research Institute, Rita-Levi Montalcini Foundation, Rome, Italy; University of Rome Tor Vergata, Rome, Italy.
Pharmacol Res. 2014 Mar;81:83-90. doi: 10.1016/j.phrs.2014.02.010. Epub 2014 Mar 12.
CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.
CHF5074是一种具有治疗阿尔茨海默病疾病修饰潜力的非甾体抗炎衍生物。本研究的目的是表征CHF5074在海马体中的电生理和代谢特征。电生理记录表明，CHF5074以剂量依赖性方式抑制CA1锥体神经元中电流诱发的重复放电。这一结果伴随着场兴奋性突触后电位的剂量依赖性降低，而对配对脉冲比率没有影响。CHF5074的作用不是由AMPA或NMDA受体介导的，因为在该化合物存在的情况下，局部应用AMPA和NMDA诱导的内向电流保持恒定。我们还提出CHF5074可能对ASIC1a受体有作用，因为用该化合物预处理后，应用pH 5.5溶液诱发的ASIC1a介导的电流会降低。此外，我们证明CHF5074处理能够在海马体切片中抵消氧糖剥夺（OGD）诱导的丙氨酸、乳酸和乙酸水平的升高。最后，如裂解的半胱天冬酶-3免疫反应性和TUNEL染色所示，CHF5074显著降低了暴露于OGD的海马神经元中的细胞凋亡。总体而言，本研究确定了CHF5074在减轻代谢性酸中毒方面的新机制，使该化合物在脑缺血情况下也可能有用。
