Inhibitory effects of N-valproyl-l-tryptophan on high potassium, low calcium and low magnesium-induced CA1 hippocampal epileptiform bursting activity in rat brain slices

Abstract

N-valproyl-L-tryptophan (VPA-Tryp), new antiepileptic drug, was tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 or 2 mM) of Valproate (VPA) or VPA-Tryp. Both burst duration and interburst frequency during and after treatment were off-line compared with baseline values. For both parameters, the latency and the length of statistically significant response periods as well as the magnitude of drug-induced responses were calculated. VPA-Tryp evoked fewer and weaker early excitatory effects than VPA on bursting activity. On the contrary, VPA-Tryp induced powerful and long-lasting inhibitory effects on epileptiform discharge in a significantly higher number of slices than VPA. In fact, greater length and magnitude of VPA-Tryp-induced inhibition on both interburst frequency and burst duration were observed. Furthermore, VPA-Tryp showed antiepileptic activity at lower concentration than VPA and, when testing both drugs at analogue concentrations, VPA-Tryp evoked responses with either shorter latency or greater effect length and magnitude than VPA.

Hippocampal Hyperexcitability is Modulated by Microtubule-Active Agent: Evidence from In Vivo and In Vitro Epilepsy Models in the Rat

“…The current results provide innovative evidence of the possible impact of microtubule cytoskeleton on hyperexcitability-based diseases. Noticeably, our experimental design exploiting two drug-free models of epileptiform activity (Stringer and Lothman, 1992 ; Sardo et al, 2012 ) allowed us to evaluate the results in an intact neuronal network, but also to exclude the influence of blood-brain barrier (BBB; Jefferys and Haas, 1982 ) and to appreciate whether any effect directly influenced hippocampal neurons. In this context, some molecular studies previously reported that, in kainate (KA)-induced epileptic state, altered microtubule formation contributed to aberrant neurogenesis in the DG with an increase in the gene expression of tubulin and microtubule-associated proteins (Represa et al, 1993 ; Pollard et al, 1994 ; Hendriksen et al, 2001 ; Sato and Abe, 2001 ).…”

“…At the end of drug administration, slices were again perfused with drug-free modified aCSF for 10 min (wash-out period). The duration and dosages of administration were chosen taking into consideration previous studies on these drugs, the reported equilibration time course of other antiepileptic drugs and pilot experiments in hippocampal slices at the depth of recording (Furukawa and Mattson, 1995 ; Petrini et al, 2004 ; Puthanveettil et al, 2008 ; Sardo et al, 2012 ).…”

“…Conversely, PAC binds to tubulin at a different site and hyperstabilizes polymerized microtubules (Gotaskie and Andreassi, 1994 ; Dinter and Berger, 1998 ; Marx et al, 2007 ). We exploited two drug-free models of epileptiform activity, the in vivo electrically-induced maximal dentate activation (MDA; Stringer and Lothman, 1992 ; Carletti et al, 2015 ), and the hippocampal epileptiform bursting activity (HEBA), characterized by in vitro neuronal burst firing evoked by changes in the electrolytic concentrations of cerebrospinal fluid (Sokolova et al, 1998 ; Sardo et al, 2012 ). Noticeably, the MDA study was primarily conducted with experimenters blind to the drugs identity to prevent the possibility of bias from interpretation of electrophysiological outcomes.…”

Brain Distribution and Modulation of Neuronal Excitability by Indicaxanthin From Opuntia Ficus Indica Administered at Nutritionally-Relevant Amounts

“…Indeed, indicaxanthin released from a barrel in 5 min at 60 nA was equivalent to 0.1 μl, corresponding approximatively to 0.34 ng (for 12 μM), 0.17 ng (for 6 μM), and 0.085 ng (for 3 μM). Apart from brain localization, microiontophoretic recordings were carried out in telencepahalic and diencephalic regions (cortex, hippocampus, striatum, globus pallidus, thalamus and subthalamic nucleus), involved in cognitive processes and mostly investigated by our group in previous electrophysiological researches (Sardo et al, 2003 , 2006 , 2009 , 2012 ; Carletti et al, 2012 , 2017 ; Plescia et al, 2014 ). Hindbrain areas were not taken in consideration for recordings because of stereotaxic limitations.…”

Studies on a new potential dopaminergic agent:in vitroBBB permeability,in vivobehavioural effects and molecular docking evaluation

“…In most of the neurological therapies, including Parkinson's disease, schizophrenia and depression, the prodrugs generally improve the efficacy of the parent drug thus decreasing the systemic and/or unwanted tissue/organspecific toxicity. Chemical manipulation of dopaminergic drugs could afford derivatives that, following bioactivation, are able to selectively bind the brain dopamine receptor subtypes, resulting thus in balance modulation of dopaminergic transmission [1][2][3].…”