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