ONO‐2506 inhibits spike–wave discharges in a genetic animal model without affecting traditional convulsive tests via gliotransmission regulation

Abstract

BACKGROUND AND PURPOSEAnticonvulsants have been developed according to the traditional neurotransmission imbalance hypothesis. However, the anticonvulsive pharmacotherapy currently available remains unsatisfactory. To develop new antiepileptic drugs with novel antiepileptic mechanisms, we have tested the antiepileptic actions of ONO-2506, a glial modulating agent, and its effects on tripartite synaptic transmission. EXPERIMENTAL APPROACHDose-dependent effects of ONO-2506 on maximal-electroshock seizure (MES), pentylenetetrazol-induced seizure (PTZ) and epileptic discharge were determined in a genetic model of absence epilepsy in mice (Cacna1a tm2Nobs/tm2Nobs strain). Antiepileptic mechanisms of ONO-2506 were analysed by examining the interaction between ONO-2506 and transmission-modulating toxins (tetanus toxin, fluorocitrate, tetrodotoxin) on release of L-glutamate, D-serine, GABA and kynurenic acid in the medial-prefrontal cortex (mPFC) of freely moving rats using microdialysis and primary cultured rat astrocytes. KEY RESULTS ONO-2506 inhibited spontaneous epileptic discharges in Cacna1atm2Nobs/tm2Nobs mice without affecting MES or PTZ. Given systemically, ONO-2506 increased basal release of GABA and kynurenic acid in the mPFC through activation of both neuronal and glial exocytosis, but inhibited depolarization-induced releases of all transmitters. ONO-2506 increased basal glial release of kynurenic acid without affecting those of L-glutamate, D-serine or GABA. However, ONO-2506 inhibited AMPA-induced releases of L-glutamate, D-serine, GABA and kynurenic acid. CONCLUSIONS AND IMPLICATIONSONO-2506 did not affect traditional convulsive tests but markedly inhibited epileptic phenomena in the genetic epilepsy mouse model. ONO-2506 enhanced release of inhibitory neuro-and gliotransmitters during the resting stage and inhibited tripartite transmission during the hyperactive stage. The results suggest that ONO-2506 is a novel potential glial-targeting antiepileptic drug. LINKED ARTICLEThis article is commented on by Onat, pp. 1086-1087 of this issue. To view this commentary visit http://dx

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“…All compounds were prepared on the day of the experiment. All drugs were perfused in MRS made up of (in mM) 145 Na + , 2.7 K + , 1.2 Ca 2+ , 1.0 Mg 2+ , and 154.4 Cl − , buffered to pH 7.4 with 2‐mM phosphate buffer and 1.1‐mM Tris buffer (Tanahashi et al, ; Yamamura et al, ). Muscimol, MK‐801, and SB269970 were dissolved in MRS directly, and lurasidone and perampanel were initially dissolved in DMSO at 1 mM.…”

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc−

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“…Perfusion experiments were started after 18 hours recovery from isoflurane anesthesia . Rats were placed into a system for freely moving animals (EICOM) that was equipped with a two‐channel swivel (TCS2‐23; ALS, Tokyo, Japan).…”

“…On day 14 of culture (DIV14), contaminating cells were removed by shaking in a standard incubator for 16 hours at 200 rpm. On DIV21, astrocytes were removed from flasks by trypsinization and were directly seeded onto translucent PET membranes (1.0 μm) in 24‐well plates (BD) at a density of 10 5 cells cm −2 for experiments . During DIV21‐DIV28, culture media were changed twice weekly and on DIV28, cultured astrocytes were washed three times using ACSF (wash‐out).…”

Carbon-based Electrode Materials for DNA Electroanalysis

“…Moreover, due to their good electrochemical stability, these sp 3 -containing carbon electrodes are suitable for long-term analysis including as the electrode of an HPLC detector for detecting various biological compounds. 95,96 …”