neurotoxicity and mechanisms of induced hyperexcitability

cysteine thiolactone (5.5 mmol/kg, i.p.). Nitro indazole isan inhibitor of neuronal nitric oxide synthase that attenuatespilocarpine-induced seizures (49). NO has been shownto modulate NMDA receptor activity by interacting withthe –SH group of its redox modulatory site via S-nitrosylation.This modification results in the downregulation ofthis receptor complex (19) and prevents the neurotoxic effectsof an excessive Ca 2+ influx during homocysteine inducedoverstimulation of NMDA and mGluRs I receptors.In addition, Kim et al. (50) demonstrated that NO ameliorateshomocysteine’s adverse effects of S-nitrosylationin cultured rat cortical neurons. Moreover, NO inducesa reduction of glutamate by activation of glial cells. Manyexperimental studies have demonstrated co-localisation ofNOS and GABA and have suggested that basal NO levelsinduce a depression of inhibition, while high concentrationsof NO increase GABA release. In contrast to homocysteine,which increases oxidative stress by the productionof reactive oxygen species, NO can act as a neuralprotector. This neuroprotective property is due to theformation of S-nitroso-L-glutathione, which is an antioxidantand NO scavenging molecule (51). However, therole of NO in epileptogenesis has been studied in differentexperimental models and reported results are highlycontradictory. Namely, the proconvulsive role of NO hasbeen demonstrated in the lindane model of convulsionsand several others (52). Thus, it seems that the activityof NO depends on the animal strain, the seizure modelemployed and the type and dose of drugs used in order tomodify cerebral NO levels.Furthermore, it has been demonstrated that when L-arginine is applied alone, it significantly increases the activityof Na + /K + -ATPase activity in the hippocampus, thecortex and the brain stem. However, when L-arginine is appliedprior to D,L homocysteine thiolactone (8 mmol/kg),this completely reverses its inhibitory effect (48). The sameholds true for its effects on Mg 2+ -ATPase activity in the ratcortex and the brain stem. L-NAME increases Na + /K + -AT-Pase activity in the cortex and the brain stem but not in thehippocampus. When L-NAME was administered prior tohomocysteine thiolactone (5.5 mmol/kg), it increased theactivity of both Na + /K + -ATPase and Mg 2+ -ATPase in therat cortex and the hippocampus.Changes in total spectral power density after ethanolalone and together with D,L-homocysteine thiolactone inadult rats were examined (53). Recording electrical activityfrom the brain represents a measure of both brain functionand dysfunction. Ethanol is used as a social substance and isthe second most widely used psychoactive substance in theworld after caffeine. The influence of ethanol on the centralnervous system depends on the dose, drinking pattern, toleranceand other factors. While chronic ethanol consumptionis followed by a series of seizures during the withdrawal period,acute ethanol intake exerts mainly inhibitory effects onthe CNS and is usually associated with an increase of seizurethreshold (54). Rasic-Markovic et al. (53) found that ethanol’saction on electrographic pattern is biphasic, which is characterisedby potentiation of epileptiform activity in one doserange and depression in another one. Low ethanol doses causingeuphoria and behavioural arousal are associated with desynchronisationof the EEG, decreases in the mean amplitudeand increases in theta and alpha activity. In addition, ethanolincreases mean total spectral power density 15 min and 30min after administration. Ethanol affects voltage-gated ionchannels, second messenger systems and a variety of differentneurotransmitter systems such as glycine, acetylcholineas well as monoamines and neuropeptides systems (55). Twomajor amino acid neurotransmitter systems, GABA and glutamate,as well as aspartate are affected by ethanol. Acute administrationof ethanol inhibits NMDA-induced Ca2+ influx,cyclic GMP production, neurotransmitter release and reducesNMDA-evoked neurotoxicity (56, 57).Pre-treatment with MK-801, which is a NMDA receptorantagonist, showed a tendency to reduced the incidenceof convulsions, latency to the first seizure onset and theseverity of seizure episodes; however, there was no statisticalsignificance when compared to the D,L-homocysteinethiolactone treated group. Nevertheless, the median numberof seizure episodes was significantly decreased by MK-801 when compared to the D,L-homocysteine thiolactonetreated group. On the other hand, ifenprodil, which is anothertype of NMDA receptor antagonist, decreased thelatency to the first seizure onset and increased the mediannumber of seizure episodes. The majority of seizure episodesin the ifenprodil (72.1%) and MK-801 (73.1%) groupswere significantly different compared to the D,L-homocysteinethiolactone treated group (36.0%). Our findingssuggest that D,L-homocysteine thiolactone induces seizuresthrough the stimulation of NMDA receptors in thecentral nervous system but other mechanisms (i.e., NOsignalling) may also be involved (58).Finally, limited data exist in the literature regarding theeffects of homocysteine and D,L-homocysteine thiolactoneon the activity of the acetylcholinesterase (AChE) enzymein the blood, but practically no data exist regarding the influenceof these compounds on this enzyme in the brainand heart. Recent results showed a significant reduction inAChE activity in all tissues obtained from rats treated withD,L-homocysteine thiolactone compared to the enzymeactivity of the control group. In addition, these results alsoshowed that the blood enzyme activity was the lowest (12%)after treatment, while the enzyme activity was slightly higherin the brain (27.8%) and heart samples (86.3%). Therefore,it was concluded that D,L-homocysteine thiolactone significantlyinhibited AChE activity in the heart and brain tissuebut not in the blood of the rat (59).Overall, these studies clearly demonstrate that acute administrationof homocysteine and especially D,L-homocysteinethiolactone elicit seizures in adult rats, affect neuronal activity,EEG recordings and behavioural responses. These effectshave been linked to the stimulation of NMDA receptors, inhibitionof the Na + /K + -ATPase, inhibition of AChE activity andthe functional involvement of NO during D,L-homocysteinethiolactone induced seizures in adult rats.7