Lindane-induced Seizures Research Articles

Osnovne karakteristike EEG epileptiformnih pražnjenja izazvanih lindanom u modelu eksperimentalnog prostatitisa

Introduction: Chronic prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is the most commonly diagnosed non-infectious prostatitis in urology. Studies have shown that CP/CPPS can induce neuroinflammation, which may result in CNS hyperexcitability and a tendency to develop epileptic seizures. Spike salvos are ictal EEG graph elements typical for the experimental model of lindane-induced seizures. There are a number of mathematical models for quantitative analysis of EEG, including the Fast Fourier Transform (FFT). It transforms the signal from time into the frequency domain, providing information on Power Spectral Densities (PSD). Aim: The aim of this study was to investigate the basic characteristics of epileptiform discharges induced by subconvulsive dose of lindane in rats, with experimentally induced CP/CPPS. Material and methods: CP/CPPS was induced by intraprostatic injection of 3% l-carrageenan in male Wistar albino rats. Animals with CP/CPPS were implanted with EEG registration electrodes, and then administered lindane (4 mg/kg, i.p, experimental group, n = 6 per group) or its solvent (DMSO, control group, n = 6 per group). An 8-channel EEG device was used in combination with software developed in the laboratory (NeuroSciLaBG). Ictal EEG epochs were extracted from the original signal and FFT analysis was performed to obtain information taking into account PSD in predefined frequency bands. Results: There was no ictal activity in the EEG of control animals. In experimental animals, ictal activity occurred and the mean duration of the ictal period was 2.06 s. FFT analysis revealed that the Alpha frequency range (7-15 Hz) was markedly dominant during ictal activity. Conclusion: The results of this study showed the characteristics of epileptiform discharges in animals with experimentally induced CP/CPPS. This study and animal model are suitable for future translational studies of the comorbidities of this syndrome.

The effects of hydrogen sulfide synthesis inhibition in lindane-induced seizures in rats: A behavioral and EEG study

Lindane-induced seizure in rats is a model of refractory generalized epilepsy. Hydrogen sulfide (H2S) is a gasotransmitter with different physiological and pathological roles. Cystathionine-?-synthase (CBS) is a major enzyme responsible for H2S production in the brain. The aim of this study was to investigate the effects of H2S production inhibition using aminooxyacetate (a CBS inhibitor) on behavioral and EEG manifestations of lindane-induced seizures. Male Wistar rats with previously implanted EEG electrodes were intraperitoneally (i.p.) treated with 4 mg/kg lindane and observed for convulsive behavior and EEG manifestations during the next 30 min. Aminooxyacetate (5, 15 and 25 mg/kg, i.p.) or saline, was injected 30 min prior to lindane. Convulsive behavior was assessed by seizure incidence, latency time and severity (grades 0-4). The number and duration of ictal periods in the EEG were also analyzed. Seizure incidence was higher in rats treated with aminooxyacetate (AOA) before lindane, but not significantly when compared with those treated only with lindane. However, AOA significantly decreased the latency time and augmented the severity of lindane-induced seizures in a dose-dependent manner. EEG analysis revealed an increased number and duration of ictal periods in rats receiving AOA prior to lindane. H2S production inhibition aggravated lindane-induced seizures, which showed a functional relationship between H2S and the effects of lindane.

Chronic prostatitis/chronic pelvic pain syndrome increases susceptibility to seizures in rats and alters brain levels of IL-1β and IL-6

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a result of interplay between psychological, immune, neurological and genetic factors, manifested by variety of urological, as well as brain-related symptoms. However, its relation with brain excitability has not been addressed. herefore, our aim was to assess susceptibility to seizures in rats with CP/CPPS.We induced CP/CPPS in adult rats by intraprostatic injection of 3% λ-carrageenan. Sham operated rats served as controls (0.9% NaCl, Sham). On day 7 upon injection, rats were treated with lindane (4 mg/kg) and observed for convulsive behavior (seizure incidence, latency and severity) and EEG manifestations (number and duration of ictal periods). Interleukin levels (IL-1β and IL-6) were measured in prostate, hippocampus, thalamus and cerebral cortex. Scrotal skin mechanical pain thresholds were determined and prostates were histologically evaluated. Animals with CP/CPPS showed significantly higher incidence, decreased latency time and augmented severity of lindane-induced seizures compared with Sham group. EEG revealed increased number of ictal periods in CP/CPPS rats. Higher levels of IL-1β and IL-6 were determined in the thalamus and cortex in CP/CPPS animals vs. Sham. IL-1β level was higher and IL-6 was lower in prostates from CP/CPPS animals comparing to Sham. CP/CPPS development was verified by histological findings of nonbacterial inflammation in the prostates, as well as by significantly decreased scrotal pain threshold in CP/CPPS animals. On the basis of this research, we concluded that CP/CPPS increases susceptibility to lindane-induced seizures in rats associated with increased level of IL-1β and IL-6 in the cortex and thalamus.

Folic acid supplementation alleviates behavioral manifestations of lindane-induced seizures

Lindane is a scabicide and pesticide that can exert neurotoxic effects such as tonic and clonic seizures that are refractory to many antiepileptic drugs. Folic acid stands out as a potential substance worth testing for its neuroprotective and in certain experimental models anticonvulsive effects. The aim of the present study was to examine the potential therapeutic value of folic acid supplementation on the behavioral characteristics of lindane-induced seizures. Adult male Wistar rats were divided into the following groups: Controls: dimethyl sulfoxide-injected (C1), saline-treated (C2); lindane (4 mg/ kg; 6 mg/kg; 8 mg/kg; L4; L6; L8, respectively); folic acid 15 mg/kg (F) and F administered 30 min prior to L4, L6, or L8 (L4F; L6F; L8F, respectively). Convulsive behavior was assessed by the incidence of seizures, seizure latency and seizure severity. Lindane administration has shown a tendency of proportional increase in seizure incidence, decrease in seizure latency and increase in seizure intensity. Pretreatment with folic acid significantly prolonged the latency period and decreased the frequency of grade 4 seizures in the L8F group when compared to the L8 group. We concluded that folic acid alleviates the behavioral manifestations of lindane-induced seizures and that it can be applied as a potential adjuvant in lindane-poisoned patients; however, further research is still needed. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 175032]

Modulatory effects of delta sleep-inducing peptide in a lindane model of generalized seizures

Delta sleep-inducing peptide (DSIP) is an endogenous peptide that is constantly present in several different brain regions. Lindane is used as a pesticide and scabicide, but it also induces seizures refractory to conventional antiepileptics. The aim of this paper was to determine whether DSIP modulates lindane-induced seizures in rats in a behavioral and electroencephalographic (EEG) study. DSIP (1 mg/kg, i.p.) or dimethyl-sulfoxide (DMSO, 0.5 ml/kg, intraperitoneally (i.p.)) were injected 30 min before lindane (8 mg/kg, i.p.) to adult male rats with previously implanted electrodes for EEG registration. During the following 30 min, the EEG was registered, and the following behavioral characteristics of seizures were observed: incidence, latency and intensity. A descriptive scale with grades from 0 to 4 provided an estimate of seizure intensity. In the EEG, the number and duration of ictal periods were analyzed using NeuroSciLaBG (Belgrade, Serbia) software. The lethality rate was also analyzed. DSIP-treated animals showed significantly modified characteristics of lindane-induced seizures when compared to the group without DSIP pretreatment (i.e. a reduced seizure intensity and a prolonged seizure latency period). However, no significant effects of DSIP on seizure incidence and lindane-induced lethality were observed. EEG analyses showed a significantly decreased number of lindane-induced EEG ictal periods in DSIP-treated animals, but with unaltered duration. These results show that DSIP favorably modulates lindane-induced seizures in rats, showing a potential to be an adjuvant component of antiepileptic treatment strategy for refractory seizures.

Sleep disruption increases seizure susceptibility: Behavioral and EEG evaluation of an experimental model of sleep apnea

Sleep disruption accompanies sleep apnea as one of its major symptoms. Obstructive sleep apnea is particularly common in patients with refractory epilepsy, but causing factors underlying this are far from being resolved. Therefore, translational studies regarding this issue are important. Our aim was to investigate the effects of sleep disruption on seizure susceptibility of rats using experimental model of lindane-induced refractory seizures.Sleep disruption in male Wistar rats with implanted EEG electrodes was achieved by treadmill method (belt speed set on 0.02m/s for working and 0.00m/s for stop mode, respectively). Animals were assigned to experimental conditions lasting 6h: 1) sleep disruption (sleep interrupted, SI; 30s working and 90s stop mode every 2min; 180cycles in total); 2) activity control (AC, 10min working and 30min stop mode, 9cycles in total); 3) treadmill chamber control (TC, only stop mode). Afterwards, the animals were intraperitoneally treated with lindane (L, 4mg/kg, SI+L, AC+L and TC+L groups) or dimethylsulfoxide (DMSO, SIc, ACc and TCc groups). Convulsive behavior was assessed by seizure incidence, latency time to first seizure, and its severity during 30min after drug administration. Number and duration of ictal periods were determined in recorded EEGs.Incidence and severity of lindane-induced seizures were significantly increased, latency time significantly decreased in animals undergoing sleep disruption (SI+L group) compared with the animals from TC+L. Seizure latency was also significantly decreased in SI+L compared to AC+L groups. Number of ictal periods were increased and duration of it presented tendency to increase in SI+L comparing to AC+L. No convulsive signs were observed in TCc, ACc and SIc groups, as well as no ictal periods in EEG.These results indicate sleep disruption facilitates induction of epileptic activity in rodent model of lindane-epilepsy enabling translational research of this phenomenon.

24. Aminooxyacetate, an inhibitor of H2S production, potentiates lindane-induced convulsions in rats

Purpose: H 2 S is a gaseous molecule recently recognized as endogenously produced neurotransmitter with different, still not well known, physiological and pathological roles. Cystathionine- β -synthase (CBS) is a major enzyme responsible for H 2 S production in the brain. The aim of this study was to investigate the effects of aminooxyacetate, potent CBS inhibitor, on convulsions induced by lindane in rats. Methods: Adult male Wistar albino rats were intraperitoneally (i.p.) treated with lindane 4 mg/kg and observed for convulsive behavioral manifestations during next 30 min. Aminooxyacetate (0.25 mmol/kg) or saline were injected 30 min prior to lindane administration. Seizure behavior was assessed by seizure incidence, latency time to first seizure onset and its severity assessed by descriptive scale with 4 grades. Results: Seizure incidence was higher in rats treated with aminooxyacetate prior to lindane, but the difference were not statistically significant comparing with those treated only with lindane. However, administration of aminooxyacetate significantly decreased the latency time to first seizure and significantly augmented severity of lindane-induced seizures. Conclusion: These results showed that aminooxyacetate, an inhibitor of H 2 S production, potentiated convulsive activity of lindane in rats.

13. L-Arginine, endogenous NO donor, potentiates lindane-induced seizures in rats

13. L-Arginine, endogenous NO donor, potentiates lindane-induced seizures in rats

Influence of NR2B-Selective NMDA Antagonist on Lindane-Induced Seizures in Rats

Ifenprodil is a novel NMDA receptor antagonist that selectively inhibits receptors containing the NR2B subunit. Lindane, a widely used pesticide and scabicide, evokes seizures mainly through the blockade of the γ-aminobutyric acid type A receptor complex. The aim of this study was to determine the effects of ifenprodil on the behavioral and electroencephalographic (EEG) manifestations of seizures in lindane-treated rats. Adult male Wistar rats with three electrodes implanted into the skull were treated intraperitoneally (i.p.) with lindane 8 mg/kg and observed for seizure behavior and EEG during the next 30 min. Seizure behavior was assessed by incidence, severity (determined by a descriptive rating scale ranging from 0 to 4) and duration of latency. Increasing doses of ifenprodil (5, 10, 20 mg/kg, i.p.) or vehicle were injected 30 min prior to lindane administration. Ifenprodil decreased the incidence and severity of lindane seizures and prolonged the latency to seizures in a dose-dependent manner. 20 mg/kg of ifenprodil significantly de- creased the incidence (p < 0.05) and severity (p < 0.05) of seizures when compared to the vehicle treatment. Latency to seizures was significantly prolonged by 10 and 20 mg/kg of ifenprodil. The estimated ED₅₀ value of ifenprodil was 15.53 (5.48–15.20) mg/kg. The lindane-induced bursts of spiking activity in EEG were not completely suppressed by the applied doses of ifenprodil. These results indicate that ifenprodil alleviates behavioral seizures and modifies EEG characteristics of lindane seizures in rats, thus showing the involvement of NMDA receptors containing the NR2B subunit in the mechanisms of lindane convulsions.

The correlation between lipid peroxidation in different brain regions and the severity of lindane-induced seizures in rats

The aim of this study was to investigate the dynamics of lipid peroxidation and the possible correlation between lipid peroxidation in different brain regions and behavioral manifestations in lindane-induced seizures in rats. Male Wistar rats were divided into the following groups: 1. control, saline-treated group; 2. dimethylsulfoxide (DMSO)-treated group; 3. lindane-treated group (8 mg/kg), intraperitoneally. Animals were sacrificed 0.5 or 4 h after treatment and the malondialdehyde level and superoxide dismutase (SOD) activity were determined in various brain regions spectrophotometrically. Behavioral changes were classified according to the descriptive scale (0--no response, 1--head nodding, lower jaw twitching; 2--myoclonic body jerks, bilateral forelimb clonus with full rearing; 3--progression to generalized clonic convulsions followed by tonic extension of fore- and hind limbs and tail; 4--status epilepticus). A significant rise in the malondialdehyde level was detected in the cerebral cortex, hippocampus, and thalamus of lindane-treated animals 0.5 and 4 h after administration (P < 0.05). SOD activity (total and mitochondrial) was significantly decreased in the hippocampus and the cortex of lindane-treated animals at both time points (P < 0.05). An initial fall in SOD activity was detected in the thalamus 4 h after lindane administration (P < 0.05). A positive correlation between seizure severity and the malondialdehyde level was found in the hippocampus at both time points (P < 0.01). These results suggest that lipid peroxidation may contribute to the neurotoxic effects of lindane in early acute lindane intoxication and that behavioral manifestations correlate with lipid peroxidation in the hippocampus of lindane-treated rats.

Dose-dependent anticonvulsive effect of ethanol on lindane-induced seizures in ratsThis article is one of a selection of papers published in the special issue Bridging the Gap: Where Progress in Cardiovascular and Neurophysiologic Research Meet.

Chronic ethanol consumption is a major risk factor for epilepsy, and seizures frequently occur during the withdrawal period. The aim of our study was to investigate effects of ethanol on lindane-induced seizures in rats. Male Wistar rats were injected i.p. with one of the following 5 treatments: (i) saline, (ii) dimethylsulfoxide, (iii) lindane (8 mg/kg) (L), (iv) ethanol in doses of 0.5 g/kg (E(0.5)), 1 g/kg (E(1)), and 2 g/kg (E(2)), and (v) groups that received ethanol 30 min before lindane (LE(0.5), LE(1), and LE(2)). Behavioral changes were described by using a descriptive scale as follows: 0, no response; 1, head nodding, lower jaw twitching; 2, myoclonic body jerks, bilateral forelimb clonus; 3, generalized tonic-clonic convulsions; 4, status epilepticus. The incidence of convulsions in the LE(2) group was significantly lower than the incidence in the L (p < 0.01) and LE(0.5) groups (p < 0.05). The median grade of convulsive behavior was significantly lower in the LE(2) (p < 0.01) and LE(1) groups (p < 0.05) compared with the L group. Latencies to the first seizure response were not significantly different among groups. ED50 of ethanol was 1.40 (1.19-1.65). Our findings suggest that ethanol decreased severity and incidence of lindane-induced seizures in a dose-dependent manner.

Correlation between electrocorticographic and motor phenomena in lindane-induced experimental epilepsy in ratsThis article is one of a selection of papers published in the special issue Bridging the Gap: Where Progress in Cardiovascular and Neurophysiologic Research Meet.

We report a study on the relation between open-field behavior and electroencephalographic (EEG) changes during lindane-induced seizures in 2-month-old adult male Wistar rats. For chronic EEG recordings and power spectra analysis, 3 electrodes were implanted into the skull. Three groups of animals, (i) saline-injected control (n = 6), (ii) DMSO-treated (n = 6), and (iii) lindane intraperitoneally administered: L(4) (4 mg/kg, n = 10), L(6) (6 mg/kg, n = 11), and L(8) (8 mg/kg, n = 11), were observed for 30 min for the occurrence of convulsive behavior. It was assessed by incidence of motor seizures, and seizure severity grade was determined by a descriptive rating scale (0, no response; 1, head nodding, lower jaw twitching; 2, myoclonic body jerks, bilateral forelimb clonus with full rearing; 3, progression to generalized clonic convulsions followed by tonic extension of fore and hind limbs and tail; 4, status epilepticus). EEG signal and spectral analyses were suitable to describe the dynamics of complex behavioral responses. Incidence and severity of epileptic manifestations, recorded as high voltage spike-wave complexes, polyspikes, sleep-like patterns in EEG, and power spectra changes, were greater in lindane-treated groups in a dose-dependent manner compared with control or DMSO-treated groups. Our results suggest good correlation between lindane-induced epileptiform activity and behavioral changes.

Dose-dependent anticonvulsive effect of ethanol on lindane-induced seizures in rats

Dose-dependent anticonvulsive effect of ethanol on lindane-induced seizures in rats

Delta sleep-inducing peptide attenuates severity of lindane-induced seizures in rats

Delta sleep-inducing peptide attenuates severity of lindane-induced seizures in rats

Ethosuximide and valproate display high efficacy against lindane-induced seizures in mice

Both lindane (γ-hexachlorocyclohexane), an organochlorine ectoparasiticide and pentylenetetrazol, used as a model of experimental epilepsy, produce convulsive seizures resulting from the blockade of the γ-aminobutyric acid (GABA A) receptor. In the present study we established the protective effects of ethosuximide and valproate against seizures induced by lindane and compared them with the well-known protective effects of these drugs against pentylenetetrazol-induced seizures in mice. Both ethosuximide and valproate afforded complete and dose-dependent protection against seizures induced by lindane. However, the potencies of these drugs were lower than those obtained against pentylenetetrazol seizures. Nevertheless, the protective efficacy of ethosuximide and valproate against experimentally induced lindane seizures may suggest possible efficacy of these drugs against seizures in lindane-poisoned patients.

Protection by conventional and new antiepileptic drugs against lindane-induced seizures and lethal effects in mice.

Toxic effects caused by the organochlorine xenobiotic lindane may result from too excessive antiscabicidal treatment and in cases of accidental or intentional poisoning. Predominant symptoms of lindane intoxication concern the central nervous system, e.g. different manifestation of hyperexcitability and epileptiform activity. The inhibition of GABA-ergic neurotransmission seems to be responsible for the convulsant activity of lindane. This study was intended to compare the protective activity of conventional and new antiepileptic drugs against convulsions and lethal effects elicited by lindane administration in mice. Diazepam, clonazepam and phenobarbital protected against full seizure pattern and lethal effects evoked by lindane. Carbamazepine, phenytoin, gabapentin, felbamate and lamotrigine inhibited only lindane-induced tonic convulsions and mortality. It may be concluded that apart from benzodiazepines, phenobarbital and, to a lesser extent, carbamazepine, phenytoin, gabapentin, felbamate and lamotrigine could be used in lindane poisoning. Vigabatrin proved completely ineffective against seizures or lethal effects elicited by lindane.

Lindane-induced convulsions in NMRI and OF1 mice: antagonism with (+) MK-801 and voltage-dependent calcium channel blockers

The convulsant profile of lindane was investigated in OF1 and NMRI mice lines in relation to other convulsants acting at the GABA A and NMDA receptor complexes. Thus, a specific GABA-gated chloride channel blocker, PTX, a GABA A receptor antagonist, PTZ, and an excitatory amino acid receptor agonist, NMDA, were used. Antagonism of the convulsant effects of each of these drugs was investigated with (+)MK-801, a blocker of the NMDA-operated cation channel, and with nifedipine, a voltage-dependent calcium channel antagonist. While no differences in potency for PTX or PTZ to induce seizures were observed between OF1 and NMRI mice. lindane was approximately 80 and 90% more polent in its ability to induce seizures and lethality, respectively, in OF1 than NMRI mice. Brain lindane concentrations at the moment of convulsion, measured after ED 100 doses of lindane (400 and 200 mg/kg for NMRI and OF1 mice, respectively), did not differ between OF1 and NMRI mice, suggesting that the different potency of lindane between these mouse lines is a consequence of pharmacokinetic factors. Furthermore, (+)MK-801 antagonized seizures induced by either lindane, PTX or PTZ with similar potencies in both mouse lines. These results, coupled with the different pharmacokinetics of lindane in OF1 and NMRI mice, suggest that the distinct effects of lindane in these mice are not mediated by different activities at either NMDA or GABA A receptor complexes. Nonetheless, nifedipine antagonized lindane-induced seizures with a three-fold higher potency in NMRI than in OF1 mice. In contrast, nifedipine failed to antagonize PTX and PTZ convulsions in both OFI and NMRI mice. These results suggest that besides the GABA A receptor complex other mechanisms related to calcium mobilization may be involved in the convulsant action of lindane.

Relationship between lindane concentration in blood and brain and convulsant response in rats after oral or intraperitoneal administration

The relationships between brain and blood concentrations of lindane and its convulsant effects have been studied in rats after different po and ip doses. A good correlation was observed between dose and the frequency and time to onset of tonic seizures, the intensity of the response and lethality. An oral ED50 (84 mg/kg) and an ip ED50 (131 mg/kg) for the half-maximal incidence rate of lindane-induced tonic seizures was determined. The incidence of response was directly proportional to the log of lindane concentration in brain and blood, with an EC50 of 5.3 micrograms/g and 1.5 micrograms/ml, respectively. The threshold concentration of lindane eliciting tonic seizures was estimated to be approximately 5 micrograms/g in brain and approximately 1.5 micrograms/ml in blood. The kinetics of lindane in brain and blood were examined after a single 60 mg/kg po or ip dose over a period from 5 min to 1 week. Concentrations of lindane in brain and blood were found to be highly correlated.