Homocysteine thiolactone-induced seizures in adult rats are aggravated by inhibition of inducible nitric oxide synthase

Abstract

<jats:p> Homocysteine and its metabolites (homocysteine thiolactone (HT)) induce seizures via different but still not well-known mechanisms. The role of nitric oxide (NO) in epileptogenesis is highly contradictory and depends on, among other factors, the source of NO production. The aim of the present study was to examine the effects of aminoguanidine, selective inhibitor of inducible NO synthase (iNOS), on HT-induced seizures. Aminoguanidine (50, 75, and 100 mg/kg, intraperitoneally (i.p.)) was injected to rats 30 min prior to inducing HT (5.5 mmol/kg, i.p.). Seizure behavior was assessed by seizure incidence, latency time to first seizure onset, number of seizure episodes, and their severity during observational period of 90 min. Number and duration of spike and wave discharges (SWDs) were determined in electroencephalogram (EEG). Seizure latency time was significantly shortened, while seizure incidence, number, and duration of HT-induced SWD in EEG significantly increased in rats receiving aminoguanidine 100 mg/kg before subconvulsive dose of HT. Aminoguanidine in a dose-dependent manner also significantly increased the number of seizure episodes induced by HT and their severity. It could be concluded that iNOS inhibitor (aminoguanidine) markedly aggravates behavioral and EEG manifestations of HT-induced seizures in rats, showing functional involvement of iNOS in homocysteine convulsive mechanisms. </jats:p>

Cysteine and homocysteine as biomarker of various diseases

“…Hcy and its metabolites homocysteine thiolactone (HT) causes seizures by different unknown mechanisms. Elevated tHcy and HT levels have been identified as risk factors for the development of numerous brain disorders including epilepsy (Hrnčić et al., 2014).…”

Multidisciplinary approach to nitric oxide signaling: Focus on gastrointestinal and central nervous system

“…Quantitative analysis of ictal activity in EEG showed congruent results with those from behavioral assessment in that study. Namely, aminoguanidine pretreatment significantly increased the number and duration of SWD induced by HCT in that study 57 .…”

“…Therefore, these results were congruent with those obtained using non-selective NOS inhibition. Contribution of iNOS-derived NO in the process of epileptogenesis elicited by HCT was recently demonstrated in this model of seizures using aminoguanidine, as selective iNOS inhibitor 57 . The results of that study showed that pretreatment with aminoguanidine (applied in the three doses) increased convulsive properties, i.e.…”

“…However, many other mechanisms are recognized as potential parts of epileptogenesis mosaic. Recently, inflammation, as well as gasotransmitters-mediated signaling processes have been identified as one of the important pathways in modulation of epileptic activity [54][55][56][57] . Our understanding of the process of epileptogenesis relies on adequate experimental models of epileptic disorder.…”

Modulation of Epileptic Activity in Rats: Focus on Sleep, Physical Exercise and Nitric Oxide–mediated Neurotransmission in a Model of Homocysteine Thiolactone–induced Seizures

“…The involvement of iNOS-derived NO in HCT-induced seizures was demonstrated using aminoguanidine, a selective iNOS inhibitor (80). Treatment with aminoguanidine increased the following behavioural seizure properties: seizure incidence, number of seizure episodes per rat and severity of HCT-induced seizures, as well as the number and duration of SWDs in the EEG.…”