scholarly journals In vitro characterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model

2020 ◽  
Author(s):  
Sukhvir K Wright ◽  
Richard E Rosch ◽  
Max A Wilson ◽  
Manoj A Upadhya ◽  
Divya R Dhangar ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Dynamical Behaviour ◽  
Receptor Antibody ◽  
Aspartate Receptor ◽  
Immunological Disorder ◽  
Ictal Activity ◽  
Modelling Techniques ◽  
Seizure Model

AbstractSeizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR-Ab) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a novel treatment compound, we developed an NMDAR-Ab mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of an NMDAR-specific neurosteroid, pregnenolone sulfate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

scholarly journals Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sukhvir K. Wright ◽  
Richard E. Rosch ◽  
Max A. Wilson ◽  
Manoj A. Upadhya ◽  
Divya R. Dhangar ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Dynamical Behaviour ◽  
Aspartate Receptor ◽  
Immunological Disorder ◽  
Ictal Activity ◽  
Modelling Techniques ◽  
Excitatory Neurotransmission ◽  
Potential Use

AbstractSeizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

scholarly journals Epileptiform Discharges With In-Vivo-Like Features in Slices of Rat Piriform Cortex With Longitudinal Association Fibers

2001 ◽  
Vol 86 (5) ◽  
pp. 2445-2460 ◽  
Author(s):  
Rezan Demir ◽  
Lewis B. Haberly ◽  
Meyer B. Jackson
Keyword(s):  
Seizure Activity ◽  
Epileptiform Activity ◽  
Piriform Cortex ◽  
Brain Slices ◽  
Epileptiform Discharges ◽  
Local Circuitry ◽  
Association Fibers ◽  
Discharge Propagation

Brain slices serve as useful models for the investigation of epilepsy. However, the preparation of brain slices disrupts circuitry and severs axons, thus complicating efforts to relate epileptiform activity in vitro to seizure activity in vivo. This issue is relevant to studies in transverse slices of the piriform cortex (PC), the preparation of which disrupts extensive rostrocaudal fiber systems. In these slices, epileptiform discharges propagate slowly and in a wavelike manner, whereas such discharges in vivo propagate more rapidly and jump abruptly between layers. The objective of the present study was to identify fiber systems responsible for these differences. PC slices were prepared by cutting along three different nearly orthogonal planes (transverse, parasagittal, and longitudinal), and epileptiform discharges were imaged with a voltage-sensitive fluorescent dye. Interictal-like epileptiform activity was enabled by either a kindling-like induction process or disinhibition with bicuculline. The pattern of discharge onset was very similar in slices cut in different planes. As described previously in transverse PC slices, discharges were initiated in the endopiriform nucleus (En) and adjoining regions in a two-stage process, starting with low-amplitude “plateau activity” at one site and leading to an accelerating depolarization and discharge onset at another nearby site. The similar pattern of onset in slices of various orientations indicates that the local circuitry and neuronal properties in and around the En, rather than long-range fibers, assume dominant roles in the initiation of epileptiform activity. Subtle variations in the onset site indicate that interneurons can fine tune the site of discharge onset. In contrast to the mode of onset, discharge propagation showed striking variations. In longitudinal slices, where rostrocaudal association fibers are best preserved, discharge propagation resembled in vivo seizure activity in the following respects: propagation was as rapid as in vivo and about two to three times faster than in other slices; discharges jumped abruptly between the En and PC; and discharges had large amplitudes in superficial layers of the PC. Cuts in longitudinal slices that partially separated the PC from the En eliminated these unique features. These results help clarify why epileptiform activity differs between in vitro and in vivo experiments and suggest that rostrocaudal pyramidal cell association fibers play a major role in the propagation of discharges in the intact brain. The longitudinal PC slice, which best preserves these fibers, is ideally suited for the study their role.

scholarly journals Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1578 ◽  
Author(s):  
Laura Walrave ◽  
Mathieu Vinken ◽  
Luc Leybaert ◽  
Ilse Smolders
Keyword(s):  
Transmembrane Protein ◽  
Epileptiform Activity ◽  
Brain Slices ◽  
High Energy ◽  
Experimental Models ◽  
Functional Coupling ◽  
Seizure Outcome ◽  
Mrna Levels

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments.

scholarly journals Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex

2018 ◽  
Vol 29 (9) ◽  
pp. 3778-3795
Author(s):  
Alexandre Pons-Bennaceur ◽  
Vera Tsintsadze ◽  
Thi-thien Bui ◽  
Timur Tsintsadze ◽  
Marat Minlebaev ◽  
...  
Keyword(s):  
Human Population ◽  
Temporal Summation ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Treatment Strategies ◽  
Anticonvulsant Treatment ◽  
A1 Receptor ◽  
Adenosine Signaling

Abstract Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/−), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/− mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

In vitro and in vivo characterization of [3H]CNS-5161—A use-dependent ligand for theN-methyl-d-aspartate receptor in rat brain

Synapse ◽  
2007 ◽  
Vol 61 (8) ◽  
pp. 577-586 ◽  
Author(s):  
Anat Biegon ◽  
Andrew Gibbs ◽  
Maritza Alvarado ◽  
Michele Ono ◽  
Scott Taylor
Keyword(s):  
Rat Brain ◽  
Aspartate Receptor ◽  
In Vivo Characterization

Correlation between in vitro and in vivo dissolution behaviour of stonewools by nonlinear modelling techniques

2007 ◽  
Vol 27 (2-3) ◽  
pp. 1837-1841 ◽  
Author(s):  
A. Bulsari ◽  
N. Bergman ◽  
I. Eusch ◽  
J. Fellman ◽  
M. Perander ◽  
...  
Keyword(s):  
Nonlinear Modelling ◽  
Dissolution Behaviour ◽  
Modelling Techniques ◽  
In Vivo Dissolution

scholarly journals Characterizing concentration-dependent neural dynamics of 4-aminopyridine-induced epileptiform activity

2018 ◽  
Author(s):  
Timothy L Myers ◽  
Oscar C González ◽  
Jacob B Stein ◽  
Maxim Bazhenov
Keyword(s):  
Epileptiform Activity ◽  
Brain Slices ◽  
Population Level ◽  
Frequency Component ◽  
Pharmacological Agents ◽  
Spatio Temporal ◽  
Dose Dependent ◽  
Array Recordings

AbstractEpilepsy remains one of the most common neurological disorders. In patients, it is characterized by unprovoked, spontaneous, and recurring seizures or ictal events. Typically, inter-ictal events or large bouts of population level activity can be measured between seizures and are generally asymptomatic. Decades of research has focused on understanding the mechanisms leading to the development of seizure-like activity using various proconvulsive pharmacological agents, including 4-aimnopyridine (4AP). However, the lack of consistency in the concentrations used for studying 4AP-induced epileptiform activity in animal models may give rise to differences in the results and interpretation thereof. Indeed, the range of 4AP concentration in both in vivo and in vitro studies varies from 3μM to 40mM. Here, we explored the effects of various 4AP concentrations on the development and characteristics of hippocampal epileptiform activity in acute mouse brain slices of either sex. Using multielectrode array recordings, we show that 4AP induces hippocampal epileptiform activity for broad range of concentrations. The frequency component and the spatio-temporal patterns of the epileptiform activity revealed a dose-dependent response. Finally, in the presence of 4AP, reduction of KCC2 co-transporter activity by KCC2 antagonist VU0240551 prevented the manifestation of the frequency component differences between different concentrations of 4AP. Overall, the study predicts that different concentrations of 4AP can result in the different mechanisms behind hippocampal epileptiform activity, of which some are dependent on the KCC2 co-transporter function.

scholarly journals Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides

2021 ◽  
Vol 22 (23) ◽  
pp. 13092
Author(s):  
Michał Abram ◽  
Marcin Jakubiec ◽  
Anna Rapacz ◽  
Szczepan Mogilski ◽  
Gniewomir Latacz ◽  
...  
Keyword(s):  
Water Soluble ◽  
Calcium Currents ◽  
In Vitro Studies ◽  
Maximal Electroshock ◽  
Induction Effect ◽  
Potential Candidate ◽  
Seizure Models ◽  
Seizure Model

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.

scholarly journals Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

2018 ◽  
Author(s):  
Jenny B. Koenig ◽  
David Cantu ◽  
Cho Low ◽  
Farzad Noubary ◽  
Danielle Croker ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Epileptiform Activity ◽  
Synaptic Activity ◽  
Network Function ◽  
Cortical Hyperexcitability ◽  
Glycolytic Inhibitor ◽  
Cortical Slices

AbstractTraumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro glycolytic inhibition decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3-5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated loss of parvalbumin-positive inhibitory interneurons. In summary, inhibition of glycolysis with 2-DG may have therapeutic potential to restore network function following TBI.One Sentence SummaryFollowing traumatic brain injury in mice, in vivo treatment with the glycolytic inhibitor 2-deoxyglucose prevented cortical network pathology including cortical hyperexcitability, changes in synaptic activity, and loss of parvalbumin-expressing GABAergic interneurons.

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