Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

Abstract

Quinolinic acid (QA) is an N-methyl-D-aspartate receptor agonist that also promotes glutamate release and inhibits glutamate uptake by astrocytes. QA is used in experimental models of seizures studying the effects of overstimulation of the glutamatergic system. The guanine-based purines (GBPs), including the nucleoside guanosine, have been shown to modulate the glutamatergic system when administered extracellularly. GBPs were shown to inhibit the binding of glutamate and analogs, to be neuroprotective under excitotoxic conditions, as well as anticonvulsant against seizures induced by glutamatergic agents, including QA-induced seizure. In this work, we studied the electrophysiological effects of guanosine against QA-induced epileptiform activity in rats at the macroscopic cortical level, as inferred by electroencephalogram (EEG) signals recorded at the epidural surface. We found that QA disrupts a prominent basal theta (4-10 Hz) activity during peri-ictal periods and also promotes a relative increase in gamma (20-50 Hz) oscillations. Guanosine, when successfully preventing seizures, counteracted both these spectral changes. MK-801, an NMDA-antagonist used as positive control, was also able counteract the decrease in theta power; however, we observed an increase in the power of gamma oscillations in rats concurrently treated with MK-801 and QA. Given the distinct spectral signatures, these results suggest that guanosine and MK-801 prevent QAinduced seizures by different network mechanisms.

Guanosine and its role in neuropathologies

“…The increase in this electrophysiological pattern is associated with the occurrence of psychotic symptoms and cognitive impairments, which are commonly induced by NMDAR antagonists such as MK-801 and ketamine [123][124][125][126]. Therefore, these results suggest that guanosine might be associated with less side effects when compared with classic NMDAR antagonists [122]. In fact, guanosine is able to prevent the locomotor stimulation induced by MK-801, but not amphetamine-or caffeine-induced hyperlocomotion, reinforcing the notion that this molecule may be a safer modulator of glutamatergic activity [127].…”

“…This observation supports the idea that the mechanism of glutamatergic modulation elicited by guanosine differs from the mechanisms of classic glutamatergic antagonists. In addition, guanosine was also able to prevent the increase in gamma oscillations induced by QA [122]. The increase in this electrophysiological pattern is associated with the occurrence of psychotic symptoms and cognitive impairments, which are commonly induced by NMDAR antagonists such as MK-801 and ketamine [123][124][125][126].…”

The Role of the Guanine-Based Purinergic System in Seizures and Epilepsy

“…In addition to clear EEG changes occurring during the seizure events, we found that quinolinic acid disrupted a prominent basal theta (4-10 Hz) activity during peri-ictal periods and promoted a relative increase in the power level at the gamma band; guanosine, when successfully preventing seizures, counteracted this effect following quinolinic acid administration. Interestingly, we observed that MK-801, a known NMDA-antagonist used as a positive control, presented different spectral effects when compared to guanosine in rats protected against quinolinic acid-induced seizures, producing large gamma oscillations following quinolinic acid administration [67]. Additionally, the combined pre-treatment with both guanosine and MK-801 in this model led to qualitatively different results than the observed when each drug was administered alone [67].…”

“…Interestingly, we observed that MK-801, a known NMDA-antagonist used as a positive control, presented different spectral effects when compared to guanosine in rats protected against quinolinic acid-induced seizures, producing large gamma oscillations following quinolinic acid administration [67]. Additionally, the combined pre-treatment with both guanosine and MK-801 in this model led to qualitatively different results than the observed when each drug was administered alone [67]. Considering these recent evidences, we suggest that a diverse mechanism of action between both drugs (guanosine versus MK-801 or perhaps other NMDA antagonists) exists and that guanosine might be related to a lower incidence of cognitive side effects than NMDA antagonists in the clinical setting.…”

“…Recently, we performed the first study addressing this issue based on epidural electroencephalogram (EEG) recordings of rats [67]. In addition to clear EEG changes occurring during the seizure events, we found that quinolinic acid disrupted a prominent basal theta (4-10 Hz) activity during peri-ictal periods and promoted a relative increase in the power level at the gamma band; guanosine, when successfully preventing seizures, counteracted this effect following quinolinic acid administration.…”