ABSTRACT
Title
Electrophysiological effects of CHF5074 on rat hippocampus: protection against in vitro OGD
Authors
D. Mango1, MB. Panico1, V. Porrini2, I. Sarnico2, M. Pizzi2, BP. Imbibo3, NB. Mercuri1, R. Nisticò1,4
1Laboratory of Experimental Neurology, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy,
2 Department of Biomedical Sciences and Biotechnologies, Universityof Brescia,
3Research and Development Department, Chiesi Farmaceutici, Parma, Italy,
4Department of Pharmacobiology, Universityof Calabria,87036 Arcavacata di Rende, Italy
Abstract
CHF5074 is a flurbiprofen analogue acting as a γ-secretase modulator endowed with selective Aβ42-lowering properties but devoid of COX inhibitory activity (Peretto et al., 2005). Accordingly, it has been shown that CHF5074 inhibits brain plaque deposition and attenuates memory deficit in AD transgenic mice (Imbimbo et al., 2009). In this work we evaluated the electrophysiological effects of CHF5074 in rat hippocampal slices. Using whole cell patch-clamp recordings, we demonstrate that CHF5074 (10–300 μmol/L) inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a reduction of field excitatory post-synaptic potentials (fEPSPs) with no effect on the paired-pulse ratio. The effects of CHF5074 are 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 CHF5074. Numerous studies have documented the neuroprotective ability of non-steroid anti-inflammatory drugs, such as flurbiprofen, in different models of experimental brain ischemia (Chechneva et al., 2006; Mishra et al., 2010). This prompted us to investigate the neuroprotective potential of CHF5074 on an in vitro model of oxygen glucose deprivation (OGD). We show that CHF5074 (1–30 μmol/L) significantly inhibited in a dose-dependent manner LDH release in neurons exposed to OGD. Interestingly, neuroprotection was still evident even when CHF5074 was added after the OGD period. Thus, the present work identifies a novel role for CHF5074 also in conditions of brain ischemia.