Inhibition of the NMDA Currents by Probenecid in Amygdaloid Kindling Epilepsy Model
Por:
González-Guevara, E, Lara-González, E, Rendon-Ochoa, E, Franco-Pérez, J, Hernández-Cerón, M, Laville, A, Pérez-Severiano, F, Martínez-de los Santos, C, Custodio, V, Bargas, J, Martínez-Lazcano, JC
Publicada:
1 sep 2024
Ahead of Print:
1 ene 2024
Resumen:
Epilepsy is characterized by a sustained depolarization and repeated discharge of neurons, attributed to overstimulation of N-methyl-D-aspartate receptors (NMDAr). Herein, we propose that probenecid (PROB), an inhibitor of the activity of some ATP binding-cassette transporters (ABC-transporters) can modify NMDAr activity and expression in amygdaloid kindled model. Some studies have suggested that NMDAr expression could be regulated by inhibiting the activity of P-glycoprotein (MDR1) and drug resistance protein-1 (MRP1). Besides, PROB was found to interact with other proteins with proven activity in the kindling model, such as TRPV2 channels, OAT1, and Panx1. Administering PROB at two doses (100 and 300 mg/kg/d) for 5 d decreased after-discharge duration and Racine behavioral scores. It also reduced the expression of NR2B and the activity of total NOS and the expression of nNOS with respect to the kindling group. In a second protocol, voltage-clamp measurements of NMDA-evoked currents were performed in CA1 hippocampal cells dissociated from control and kindled rats. PROB produced a dose-dependent reduction in NMDA-evoked currents. In neurons from kindled rats, a residual NMDA-evoked current was registered with respect to control animals, while a reduction in NMDA-evoked currents was observed in the presence of 20 mM PROB. Finally, we evaluated the expression of MRP1 and MDR1 in order to establish a relationship between the reduction of kindling parameters, the inhibition of NMDA-type currents, and the expression of these transporters. Based on our results, we conclude that at the concentrations used, PROB inhibits currents evoked by NMDA in dissociated neurons of control and kindled rats. In the kindling model, at the tested doses, PROB decreases the after-discharge duration and Racine behavioral score in the kindling model. We propose a mechanism that could be dependent on the expression of ABC-type transporters.
Filiaciones:
González-Guevara, E:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Inst Nacl Neurol & Neurocirugia MVS, Lab Neurofarmacol Mol & Nanotecnol, Insurgentes Sur 3877, Mexico City 14629, Mexico
Lara-González, E:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, Mexico
Northwestern Univ, Feinberg Sch Med, Dept Neurosci, Chicago, IL 60611 USA
Rendon-Ochoa, E:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, Mexico
Univ Nacl Autonoma Mexico, Fac Estudios Super Iztacala, Lab Psicofarmacol, Tlalnepantla 54090, Mexico
Franco-Pérez, J:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Inst Nacl Neurol & Neurocirugia MVS, Lab Neuropatol Vasc, Mexico City 14629, Mexico
Hernández-Cerón, M:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Inst Nacl Neurol & Neurocirugia MVS, Lab Neuroquim, Mexico City 14629, Mexico
Laville, A:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, Mexico
Pérez-Severiano, F:
Inst Nacl Neurol & Neurocirugia MVS, Lab Neurofarmacol Mol & Nanotecnol, Insurgentes Sur 3877, Mexico City 14629, Mexico
Martínez-de los Santos, C:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Inst Nacl Neurol & Neurocirugia MVS, Dept Neuroanestesiol, Mexico City 14269, Mexico
Custodio, V:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Bargas, J:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, Mexico
Martínez-Lazcano, JC:
Inst Nacl Neurol & Neurocirugia MVS, Dept Neurofisiol, Mexico City 14629, Mexico
Inst Nacl Neurol & Neurocirugia MVS, Lab Neurofarmacol Mol & Nanotecnol, Insurgentes Sur 3877, Mexico City 14629, Mexico
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