title: Electrophysiological and metabolic effects of CHF5074 in the hippocampus: protection against in vitro ischemia.
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.
authors.affiliation: IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Mango
authors.affiliation: European Brain Research Institute, Rita-Levi Montalcini Foundation, Rome, Italy; University of Rome Tor Vergata, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barbato
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Piccirilli
authors.affiliation: IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: M B
authors.initials: MB
authors.lastname: Panico
authors.affiliation: European Brain Research Institute, Rita-Levi Montalcini Foundation, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Feligioni
authors.affiliation: IRCCS Santa Lucia Foundation, Rome, Italy; Sapienza University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Schepisi
authors.affiliation: Sapienza University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Graziani
authors.affiliation: University of Brescia, Brescia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Porrini
authors.affiliation: University of Brescia, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Benarese
authors.affiliation: University of Brescia, Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lanzillotta
authors.affiliation: University of Brescia, Brescia, Italy; IRCCS San Camillo, Venice, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pizzi
authors.affiliation: University of Milan, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pieraccini
authors.affiliation: University of Milan, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sironi
authors.affiliation: IRCCS Mondino National Neurological Institute, Pavia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Blandini
authors.affiliation: Sapienza University of Rome, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: IRCCS Santa Lucia Foundation, Rome, Italy; University of Rome Tor Vergata, Rome, Italy.
authors.forename: N B
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: Research and Development Department, Chiesi Farmaceutici, Parma, Italy.
authors.forename: B P
authors.initials: BP
authors.lastname: Imbimbo
authors.affiliation: IRCCS Santa Lucia Foundation, Rome, Italy; Sapienza University of Rome, Rome, Italy. Electronic address: robert.nistico@uniroma1.it.
authors.forename: R
authors.initials: R
authors.lastname: Nisticò
mesh_terms: D000085:Acetates / Q000378:metabolism; D000409:Alanine / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology*; D055724:Electrophysiological Phenomena; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017208:Rats, Wistar
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003521:Cyclopropanes; D018696:Neuroprotective Agents; D001224:Aspartic Acid; D019344:Lactic Acid; D005480:Flurbiprofen; C000179:N-acetylaspartate; D000409:Alanine
keywords: ASICs; CHF5074; Electrophysiology; Hippocampus; Neuroprotection