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Neurology India 2021Epilepsy is a common neurological disease, although its etiology and pathophysiology are not yet fully understood. Oxidative stress plays a key role in the pathogenesis...
INTRODUCTION
Epilepsy is a common neurological disease, although its etiology and pathophysiology are not yet fully understood. Oxidative stress plays a key role in the pathogenesis of many neurological diseases, including epilepsy, and there have been many studies reporting that antiepileptic medicines with neuroprotective and antioxidant activity inhibit free oxygen radicals. This study evaluates the effects of tempol on epileptic activity through behavioral parameters in acute picrotoxin (Ptx) models.
MATERIALS AND METHODS
This experimental study was conducted on 42 adult male Wistar Albino rats weighing 450-500 g. Ptx (2.5 mg/kg) was injected i.p. as a single dose and observed for one hour to establish the acute Ptx model. Following injection, the animals were observed for 30 min in glass observation cages measuring 35 cm x 35 cm x 35 cm.
RESULTS
In picrotoxin-induced epilepsy, the total number of seizures and the total duration of seizures were decreased significantly with Ptx + tempol 100 mg/kg and Ptx + Tempol 150 mg/kg. The seizure phases were reduced significantly by Ptx + tempol 150 mg/kg (P < 0.05).
CONCLUSION
Tempol 100 mg/kg and tempol 150 mg/kg are found to be effective in epilepsy models caused by Ptx, with tempol 150 mg/kg found especially to be more effective.
Topics: Animals; Cyclic N-Oxides; Disease Models, Animal; Epilepsy; Male; Picrotoxin; Rats; Rats, Wistar; Seizures; Spin Labels
PubMed: 33904467
DOI: 10.4103/0028-3886.314542 -
PLoS Computational Biology Jul 2020We previously proposed, on theoretical grounds, that the cerebellum must regulate the dimensionality of its neuronal activity during motor learning and control to cope...
We previously proposed, on theoretical grounds, that the cerebellum must regulate the dimensionality of its neuronal activity during motor learning and control to cope with the low firing frequency of inferior olive neurons, which form one of two major inputs to the cerebellar cortex. Such dimensionality regulation is possible via modulation of electrical coupling through the gap junctions between inferior olive neurons by inhibitory GABAergic synapses. In addition, we previously showed in simulations that intermediate coupling strengths induce chaotic firing of inferior olive neurons and increase their information carrying capacity. However, there is no in vivo experimental data supporting these two theoretical predictions. Here, we computed the levels of synchrony, dimensionality, and chaos of the inferior olive code by analyzing in vivo recordings of Purkinje cell complex spike activity in three different coupling conditions: carbenoxolone (gap junctions blocker), control, and picrotoxin (GABA-A receptor antagonist). To examine the effect of electrical coupling on dimensionality and chaotic dynamics, we first determined the physiological range of effective coupling strengths between inferior olive neurons in the three conditions using a combination of a biophysical network model of the inferior olive and a novel Bayesian model averaging approach. We found that effective coupling co-varied with synchrony and was inversely related to the dimensionality of inferior olive firing dynamics, as measured via a principal component analysis of the spike trains in each condition. Furthermore, for both the model and the data, we found an inverted U-shaped relationship between coupling strengths and complexity entropy, a measure of chaos for spiking neural data. These results are consistent with our hypothesis according to which electrical coupling regulates the dimensionality and the complexity in the inferior olive neurons in order to optimize both motor learning and control of high dimensional motor systems by the cerebellum.
Topics: Action Potentials; Animals; Bayes Theorem; Cerebellum; Computer Simulation; Female; Gap Junctions; Models, Neurological; Models, Statistical; Neurons; Nonlinear Dynamics; Olivary Nucleus; Picrotoxin; Probability; Purkinje Cells; Rats; Rats, Sprague-Dawley; Synapses; gamma-Aminobutyric Acid
PubMed: 32730255
DOI: 10.1371/journal.pcbi.1008075 -
The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain.Molecular Brain Sep 2021Assessment of neural activity in the specific brain area is critical for understanding the circuit mechanisms underlying altered brain function and behaviors. A number...
Assessment of neural activity in the specific brain area is critical for understanding the circuit mechanisms underlying altered brain function and behaviors. A number of immediate early genes (IEGs) that are rapidly transcribed in neuronal cells in response to synaptic activity have been used as markers for neuronal activity. However, protein detection of IEGs requires translation, and the amount of newly synthesized gene product is usually insufficient to detect using western blotting, limiting their utility in western blot analysis of brain tissues for comparison of basal activity between control and genetically modified animals. Here, we show that the phosphorylation status of eukaryotic elongation factor-2 (eEF2) rapidly changes in response to synaptic and neural activities. Intraperitoneal injections of the GABA A receptor (GABAR) antagonist picrotoxin and the glycine receptor antagonist brucine rapidly dephosphorylated eEF2. Conversely, potentiation of GABARs or inhibition of AMPA receptors (AMPARs) induced rapid phosphorylation of eEF2 in both the hippocampus and forebrain of mice. Chemogenetic suppression of hippocampal principal neuron activity promoted eEF2 phosphorylation. Novel context exploration and acute restraint stress rapidly modified the phosphorylation status of hippocampal eEF2. Furthermore, the hippocampal eEF2 phosphorylation levels under basal conditions were reduced in mice exhibiting epilepsy and abnormally enhanced excitability in CA3 pyramidal neurons. Collectively, the results indicated that eEF2 phosphorylation status is sensitive to neural activity and the ratio of phosphorylated eEF2 to total eEF2 could be a molecular signature for estimating neural activity in a specific brain area.
Topics: Animals; Brain; CA3 Region, Hippocampal; Eukaryotic Initiation Factor-2; Genes, Reporter; Mice; Muscimol; Nerve Tissue Proteins; Phosphorylation; Picrotoxin; Prosencephalon; Protein Processing, Post-Translational; Pyramidal Cells; Quinoxalines; Restraint, Physical; Stress, Physiological; Strychnine
PubMed: 34526091
DOI: 10.1186/s13041-021-00852-0 -
Scientific Reports May 2021Mounting evidence implicates dysfunctional GABAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse...
Mounting evidence implicates dysfunctional GABAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS). The specific origin and nature of such dysfunction is still under investigation, which is an issue with practical consequences to preclinical and clinical research, as well as to the care of individuals with DS and anxiety disorder or those experiencing seizures in emergency room settings. Here, we investigated the effects of GABAR positive allosteric modulation (PAM) by diazepam on brain activity, synaptic plasticity, and behavior in Ts65Dn mice. We found Ts65Dn mice to be less sensitive to diazepam, as assessed by electroencephalography, long-term potentiation, and elevated plus-maze. Still, diazepam pre-treatment displayed typical effectiveness in reducing susceptibility and severity to picrotoxin-induced seizures in Ts65Dn mice. These findings fill an important gap in the understanding of GABAergic function in a key model of DS.
Topics: Animals; Diazepam; Disease Models, Animal; Down Syndrome; Electrophysiological Phenomena; Female; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Picrotoxin; Seizures; Synaptic Transmission
PubMed: 33947925
DOI: 10.1038/s41598-021-89011-y -
Epilepsia 2003Generalized epilepsy involves abnormally synchronized activity in large-scale neuronal networks. Burst firing of action potentials is a potent mechanism for increasing... (Review)
Review
Generalized epilepsy involves abnormally synchronized activity in large-scale neuronal networks. Burst firing of action potentials is a potent mechanism for increasing neural synchrony and is thought to enhance cortical and thalamic rhythmic network activity. Absence seizures, a form of generalized epilepsy, occur in children as brief 5- to 10-s periods of behavioral arrest associated with massive 3- to 4-Hz spike-wave discharges in cortical and thalamic networks. Prior research has shown that enhanced burst firing may be crucial for the transition from normal to epileptic activity. Can enhanced burst firing in one region of the nervous system, such as the cortex, transform the entire thalamocortical network from normal activity to spike-and-wave seizures? Enhanced burst firing in corticothalamic neurons may increase gamma-aminobutyric acid-B (GABAB) receptor activation in the thalamus, leading to the slower, more synchronous oscillations seen in spike-and-wave seizures. Does "generalized" spike-wave activity homogeneously involve the entire brain, or are there crucial nodes that are more important than others for the generation and behavioral manifestations of generalized seizures? Animal and human data suggest that so-called generalized seizures involve selective thalamocortical networks while sparing others. A greater understanding of these molecular and network mechanisms will ultimately lead to improved targeted therapies for generalized epilepsy.
Topics: Animals; Brain Mapping; Cerebral Cortex; Electric Stimulation; Electroencephalography; Electrophysiology; Epilepsy, Generalized; Ferrets; GABA Antagonists; Humans; Magnetic Resonance Imaging; Models, Neurological; Neural Pathways; Picrotoxin; Sodium Channels; Syndrome; Thalamus
PubMed: 12752456
DOI: 10.1046/j.1528-1157.44.s.2.2.x -
Acta Neurobiologiae Experimentalis 1990Assemblies of electrodes and a cannula were stereotaxically implanted in the ventromedial (VMH), lateral (LHA) and paraventricular (PVH) hypothalamic areas in male...
Assemblies of electrodes and a cannula were stereotaxically implanted in the ventromedial (VMH), lateral (LHA) and paraventricular (PVH) hypothalamic areas in male albino rats. Electrical activity of these regions was recorded electrographically before and following intracranial injection (ICI) of GABA, muscimol and picrotoxin. In another set of animals, food intake and water intake were also measured. The activity of the ventromedial hypothalamus changed from slow to fast after ICI of GABA and picrotoxin and fast to slow after muscimol. The activity of the lateral hypothalamus changed from slow to fast with ICI of muscimol and picrotoxin and from fast to slow with GABA, while that of the paraventricular hypothalamic nucleus changed from slow to fast with ICI GABA and fast to slow with muscimol and picrotoxin. ICI of GABA into VMH and LHA and muscimol in VMH, LHA and PVH caused a decrease in food intake. Water intake was also decreased after ICI of GABA in PVH and muscimol in LHA and PVH. On the opposite picrotoxin increased food intake in VMA and LHA and water intake in PVH. The possible interaction of GABAergic drugs with the areas of the brain controlling feeding and drinking is being discussed.
Topics: Action Potentials; Animals; Drinking Behavior; Feeding Behavior; Hypothalamus; Male; Microinjections; Muscimol; Picrotoxin; Rats; Rats, Inbred Strains; gamma-Aminobutyric Acid
PubMed: 2220435
DOI: No ID Found -
Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists.Neurotoxicology Jan 2020Previous studies demonstrated that pentylenetetrazole (PTZ), a GABA type A receptor (GABAR) antagonist, elicits seizure-like phenotypes in larval zebrafish (Danio...
Previous studies demonstrated that pentylenetetrazole (PTZ), a GABA type A receptor (GABAR) antagonist, elicits seizure-like phenotypes in larval zebrafish (Danio rerio). Here, we determined whether the GABAR antagonists, tetramethylenedisulfotetramine (TETS) and picrotoxin (PTX), both listed as credible chemical threat agents, similarly trigger seizures in zebrafish larvae. Larvae of three, routinely used laboratory zebrafish lines, Tropical 5D, NHGRI and Tupfel long fin, were exposed to varying concentrations of PTZ (used as a positive control), PTX or TETS for 20 min at 5 days post fertilization (dpf). Acute exposure to PTZ, PTX or TETS triggered seizure behavior in the absence of morbidity or mortality. While the concentration-effect relationship for seizure behavior was similar across zebrafish lines for each GABAR antagonist, significantly less TETS was required to trigger seizures relative to PTX or PTZ. Recordings of extracellular field potentials in the optic tectum of 5 dpf Tropical 5D zebrafish confirmed that all three GABAR antagonists elicited extracellular spiking patterns consistent with seizure activity, although the pattern varied between chemicals. Post-exposure treatment with the GABAR positive allosteric modulators (PAMs), diazepam, midazolam or allopregnanolone, attenuated seizure behavior and activity but did not completely normalize electrical field recordings in the optic tectum. These data are consistent with observations of seizure responses in mammalian models exposed to these same GABAR antagonists and PAMs, further validating larval zebrafish as a higher throughput-screening platform for antiseizure therapeutics, and demonstrating its appropriateness for identifying improved countermeasures for TETS and other convulsant chemical threat agents that trigger seizures via GABAR antagonism.
Topics: Animals; Brain; Bridged-Ring Compounds; Drug Evaluation, Preclinical; GABA-A Receptor Antagonists; Pentylenetetrazole; Picrotoxin; Seizures; Zebrafish
PubMed: 31811871
DOI: 10.1016/j.neuro.2019.12.001 -
The Journal of Biological Chemistry Jun 2007Contrary to its effect on the gamma-aminobutyric acid type A and C receptors, picrotoxin antagonism of the alpha1 homomeric glycine receptors (GlyRs) has been shown to... (Comparative Study)
Comparative Study
Contrary to its effect on the gamma-aminobutyric acid type A and C receptors, picrotoxin antagonism of the alpha1 homomeric glycine receptors (GlyRs) has been shown to be non-use-dependent and nonselective between the picrotoxin components picrotoxinin and picrotin. Picrotoxin antagonism of the embryonic alpha2 homomeric GlyR is known to be use-dependent and reflects a channel-blocking mechanism, but the selectivity of picrotoxin antagonism of the embryonic alpha2 homomeric GlyRs between picrotoxinin and picrotin is unknown. Hence, we used the patch clamp recording technique in the outside-out configuration to investigate, at the single channel level, the mechanism of picrotin- and picrotoxinin-induced inhibition of currents, which were evoked by the activation of alpha2 homomeric GlyRs stably transfected into Chinese hamster ovary cells. Although both picrotoxinin and picrotin inhibited glycine-evoked outside-out currents, picrotin had a 30 times higher IC50 than picrotoxinin. Picrotin-evoked inhibition displayed voltage dependence, whereas picrotoxinin did not. Picrotoxinin and picrotin decreased the mean open time of the channel in a concentration-dependent manner, indicating that these picrotoxin components can bind to the receptor in its open state. When picrotin and glycine were co-applied, a large rebound current was observed at the end of the application. This rebound current was considerably smaller when picrotoxinin and glycine were co-applied. Both picrotin and picrotoxinin were unable to bind to the unbound conformation of the receptor, but both could be trapped at their binding site when the channel closed during glycine dissociation. Our data indicate that picrotoxinin and picrotin are not equivalent in blocking alpha2 homomeric GlyR.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Evoked Potentials; GABA Antagonists; Glycine; Humans; Membrane Potentials; Patch-Clamp Techniques; Picrotoxin; Protein Binding; Protein Conformation; Receptors, Glycine; Sesterterpenes; Transfection
PubMed: 17405877
DOI: 10.1074/jbc.M701502200 -
British Journal of Pharmacology Feb 2017Prefrontal dopamine release by the combined activation of 5-HT and sigma-1 (σ ) receptors is enhanced by the GABA receptor antagonist picrotoxin in mice. Here, we...
BACKGROUND AND PURPOSE
Prefrontal dopamine release by the combined activation of 5-HT and sigma-1 (σ ) receptors is enhanced by the GABA receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.
EXPERIMENTAL APPROACH
Male mice were treated with picrotoxin to decrease GABA receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically.
KEY RESULTS
Picrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter-induced increase in c-Fos expression in the nucleus accumbens. Picrotoxin-induced anhedonia was ameliorated by fluvoxamine and S-(+)-fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ receptor. The effect of fluvoxamine was blocked by a 5-HT or a σ receptor antagonist, and co-administration of the σ receptor agonist (+)-SKF-10047 and the 5-HT receptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ receptor, did not affect picrotoxin-induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin-induced anhedonia.
CONCLUSION AND IMPLICATIONS
Picrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT and σ receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice.
Topics: Anhedonia; Animals; Dose-Response Relationship, Drug; Female; Male; Mice; Picrotoxin; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 27987210
DOI: 10.1111/bph.13692 -
BMC Neuroscience Aug 2010Picrotoxin blocks GABAA receptors, whose activation typically inhibits neuronal firing activity. We recently found that rats learn to selectively self-administer...
Administration of the GABAA receptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures. Supramammillary picrotoxin and c-Fos expression.
BACKGROUND
Picrotoxin blocks GABAA receptors, whose activation typically inhibits neuronal firing activity. We recently found that rats learn to selectively self-administer picrotoxin or bicuculline, another GABAA receptor antagonist, into the supramammillary nucleus (SuM), a posterior hypothalamic structure localized anterior to the ventral tegmental area. Other drugs such as nicotine or the excitatory amino acid AMPA are also self-administered into the SuM. The SuM appears to be functionally linked with the mesolimbic dopamine system and is closely connected with other brain structures that are implicated in motivational processes, including the prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Here, we hypothesized that these brain structures are activated by picrotoxin injections into the SuM.
RESULTS
Picrotoxin administration into the SuM markedly facilitated locomotion and rearing. Further, it increased c-Fos expression in this region, suggesting blockade of tonic inhibition and thus the disinhibition of local neurons. This manipulation also increased c-Fos expression in structures including the ventral tegmental area, medial shell of the nucleus accumbens, medial prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus.
CONCLUSIONS
Picrotoxin administration into the SuM appears to disinhibit local neurons and recruits activation of brain structures associated with motivational processes, including the mesolimbic dopamine system, prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. These regions may be involved in mediating positive motivational effects triggered by intra-SuM picrotoxin.
Topics: Animals; Electric Stimulation; Functional Laterality; GABA Antagonists; Immunohistochemistry; Male; Mammillary Bodies; Microinjections; Motor Activity; Picrotoxin; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, GABA-A; Reward
PubMed: 20716371
DOI: 10.1186/1471-2202-11-101