Gut neurotoxin p-cresol induces differential expression of GLUN2B and GLUN2A subunits of the NMDA receptor in the hippocampus and nucleus accumbens in healthy and audiogenic seizure-prone rats.

Mislocalization and abnormal expression of N-methyl-D-aspartate glutamate receptor (NMDAR) subunits is observed in several brain disorders and pathological conditions. Recently, we have shown that intraperitoneal injection of the gut neurotoxin p-cresol induces autism-like behavior and accelerates seizure reactions in healthy and epilepsy-prone rats, respectively. In this study, we evaluated the expression of GLUN2B and GLUN2A NMDAR subunits, and assessed the activity of cAMP-response element binding protein (CREB) and Rac1 in the hippocampi and nucleus accumbens of healthy and epilepsy-prone rats following p-cresol administration. We have found that subchronic intraperitoneal injection of p-cresol induced differential expression of GLUN2B and GLUN2A between the two brain regions, and altered the GLUN2B/GLUN2A ratio, in rats in both groups. Moreover, p-cresol impaired CREB phosphorylation in both brain structures and stimulated Rac activity in the hippocampus. These data indicate that p-cresol differently modulates the expression of NMDAR subunits in the nucleus accumbens and hippocampi of healthy and epilepsy-prone rats. We propose that these differences are due to the specificity of interactions between dopaminergic and glutamatergic pathways in these structures.

Concentration- and time-dependent effects of myo-inositol on evoked epileptic afterdischarge in the hippocampus in vivo.

Epilepsy is one of the most widespread neurological diseases characterized by spontaneous recurrent seizures. There is no cure for epilepsy, and available pharmacological treatments with anti-seizure drugs are only symptomatic. Moreover, about third of epilepsy patients are resistant to the anti-seizure drugs. Thus, it is essential to discover new anti-epilepsy drugs. Recently, myo-inositol has been identified as a promising antiepileptic compound. In the present study, using electrophysiological method, we examined for the first time, the effect of myo-inositol on the generation of epileptic afterdischarges in the hippocampus evoked by a local electrical stimulation. This was achieved by implanting two electrodes with a cannula into the same dorsal hippocampus, which allowed for simultaneous local injection of myo-inositol or saline and afterdischarges induction and recording from the same hippocampus. We found that myo-inositol has time- and concentration-dependent effects on the evoked afterdischarges. Specifically, 5 minutes after 1 M myo-inositol infusion, the afterdischarges duration was significantly decreased as compared to preinjection durations in the same animals and also as compared to preinjection level durations in saline injected or contralateral hippocampus myo-inositol infused animals. Further, 0.055 M myo-inositol significantly decreased afterdischarges duration at 5 minutes as compared to 40 minutes post-injection. At both concentrations, the afterdischarges duration recovered to the pre-injection value at 40 minutes after the myo-inositol injection. The present data, taken together with our previous results, strongly suggest that myo-inositol has significant local seizure-suppressant effect.