2. Academic Validation
  3. Electrophysiological and metabolic effects of CHF5074 in the hippocampus: protection against in vitro ischemia

Electrophysiological and metabolic effects of CHF5074 in the hippocampus: protection against in vitro ischemia

  • Pharmacol Res. 2014 Mar;81:83-90. doi: 10.1016/j.phrs.2014.02.010.
D Mango 1,  G Barbato 2,  S Piccirilli 3,  M B Panico 1,  M Feligioni 4,  C Schepisi 5,  M Graziani 6,  V Porrini 7,  M Benarese 7,  A Lanzillotta 7,  M Pizzi 8,  S Pieraccini 9,  M Sironi 9,  F Blandini 10,  F Nicoletti 6,  N B Mercuri 11,  B P Imbimbo 12,  R Nisticò 13
Affiliations

Affiliations

  • 1 IRCCS Santa Lucia Foundation, Rome, Italy.
  • 2 European Brain Research Institute, Rita-Levi Montalcini Foundation, Rome, Italy; University of Rome Tor Vergata, Rome, Italy.
  • 3 University of Rome Tor Vergata, Rome, Italy.
  • 4 European Brain Research Institute, Rita-Levi Montalcini Foundation, Rome, Italy.
  • 5 IRCCS Santa Lucia Foundation, Rome, Italy; Sapienza University of Rome, Rome, Italy.
  • 6 Sapienza University of Rome, Rome, Italy.
  • 7 University of Brescia, Brescia, Italy.
  • 8 University of Brescia, Brescia, Italy; IRCCS San Camillo, Venice, Italy.
  • 9 University of Milan, Milan, Italy.
  • 10 IRCCS Mondino National Neurological Institute, Pavia, Italy.
  • 11 IRCCS Santa Lucia Foundation, Rome, Italy; University of Rome Tor Vergata, Rome, Italy.
  • 12 Research and Development Department, Chiesi Farmaceutici, Parma, Italy.
  • 13 IRCCS Santa Lucia Foundation, Rome, Italy; Sapienza University of Rome, Rome, Italy. Electronic address: robert.nistico@uniroma1.it.
PMID: 24630950 DOI: 10.1016/j.phrs.2014.02.010
Abstract

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.

Keywords

ASICs; CHF5074; Electrophysiology; Hippocampus; Neuroprotection.

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