scholarly journals Equilibrative Nucleoside Transporters-1 Inhibitors Act as Anti-epileptic Agents by Inhibiting Glutamatergic Transmission

2020 ◽  
Vol 14 ◽  
Author(s):  
Shih-Yin Ho ◽  
I-Chun Chen ◽  
Kai-Chieh Chang ◽  
Hsiao-Ru Lin ◽  
Che-Wen Tsai ◽  
...  
Keyword(s):  
Granule Cells ◽  
Nucleoside Transporters ◽  
Myoclonic Epilepsy ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Patch Clamp Technique ◽  
Kindling Model ◽  
Equilibrative Nucleoside Transporters ◽  
Epilepsy Models ◽  
The Brain

Background and Purpose: Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain. This study was aimed to prove the anti-epileptic effect of BBB permeable ENT-1 inhibitors, JMF1907 and J4, on animal models of various epilepsy, and the mechanisms that are involved.Experimental Approach: Maximal electroshock seizure (MES), pentylenetetrazol (PTZ)-induced seizure and kindling models were used as mouse models of generalized tonic-clonic epilepsy, generalized myoclonic epilepsy, and partial epilepsy, respectively. The epilepsy frequency, duration, and Racine score were evaluated. Whole-cell recordings were made from the hippocampal dentate granule cells by using a patch-clamp technique in the brain slice of the mice.Key Results: In MES, JMF1907 at a dose of 5 mg kg–1 was efficacious in decreasing hindlimb extension, while J4 did not decrease hindlimb extension until a higher dose (10 mg kg–1). Both JMF1907 and J4 were more potent in lengthening onset latency than ethosuximide (ETH) in PTZ-induced myoclonic epilepsy model, whereas ETH had better effects on the Racine score. In kindling model, JMF1907 and J4 at a dose of 1 mg kg–1 had effects on seizure frequency and duration, and the effects of JMF1907 were comparable with those of carbamazepine. Both JMF1907 and J4 can reduce the glutamatergic spontaneous excitatory post-synaptic currents (sEPSCs) frequency. The maximal inhibition was about 50% for JMF1907 at a concentration of 1 μg L–1, whereas J4 only inhibited 40% of sEPSCs frequency at a dose of 10 μg L–1.Conclusion and Implications: ENT-1 inhibitors, JMF1907 and J4, showed anti-epileptic effects in different epilepsy models and the effects involved pre-synaptic neuronal modulation.

Implantable neural interfaces

2018 ◽  
Author(s):  
Stefano Vassanelli
Keyword(s):  
Brain Function ◽  
Large Scale ◽  
Ionic Channels ◽  
Patch Clamp Technique ◽  
Advantages And Disadvantages ◽  
Optogenetic Stimulation ◽  
Physical Interfaces ◽  
The Brain

Establishing direct communication with the brain through physical interfaces is a fundamental strategy to investigate brain function. Starting with the patch-clamp technique in the seventies, neuroscience has moved from detailed characterization of ionic channels to the analysis of single neurons and, more recently, microcircuits in brain neuronal networks. Development of new biohybrid probes with electrodes for recording and stimulating neurons in the living animal is a natural consequence of this trend. The recent introduction of optogenetic stimulation and advanced high-resolution large-scale electrical recording approaches demonstrates this need. Brain implants for real-time neurophysiology are also opening new avenues for neuroprosthetics to restore brain function after injury or in neurological disorders. This chapter provides an overview on existing and emergent neurophysiology technologies with particular focus on those intended to interface neuronal microcircuits in vivo. Chemical, electrical, and optogenetic-based interfaces are presented, with an analysis of advantages and disadvantages of the different technical approaches.

scholarly journals Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

2021 ◽  
Author(s):  
Kinga K. Borowicz-Reutt ◽  
Monika Banach ◽  
Monika Rudkowska ◽  
Anna Stachniuk
Keyword(s):  
Antiepileptic Drugs ◽  
Second Generation ◽  
Antidepressant Drug ◽  
Experimental Models ◽  
Long Term Memory ◽  
Avoidance Task ◽  
Maximal Electroshock ◽  
Term Memory ◽  
The Brain

Abstract Background Due to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. Materials and methods As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry. Results Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. Conclusion Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

scholarly journals Testicular disposition of clofarabine in rats is dependent on equilibrative nucleoside transporters

2021 ◽  
Vol 9 (4) ◽  
Author(s):  
Siennah R. Miller ◽  
Joseph L. Jilek ◽  
Meghan E. McGrath ◽  
Raymond K. Hau ◽  
Erin Q. Jennings ◽  
...  
Keyword(s):  
Nucleoside Transporters ◽  
Equilibrative Nucleoside Transporters

scholarly journals The brain-specific RasGEF very-KIND is required for normal dendritic growth in cerebellar granule cells and proper motor coordination

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0173175 ◽  
Author(s):  
Kanehiro Hayashi ◽  
Asako Furuya ◽  
Yuriko Sakamaki ◽  
Takumi Akagi ◽  
Yo Shinoda ◽  
...  
Keyword(s):  
Dendritic Growth ◽  
Motor Coordination ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cerebellar Granule ◽  
The Brain

scholarly journals Efficient generation of reciprocal signals by inhibition

2012 ◽  
Vol 107 (9) ◽  
pp. 2453-2462 ◽  
Author(s):  
Sung-min Park ◽  
Esra Tara ◽  
Kamran Khodakhah
Keyword(s):  
Purkinje Cells ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Cell Activity ◽  
Common Mechanism ◽  
Input Output ◽  
Firing Rates ◽  
Neuronal Computation ◽  
The Brain

Reciprocal activity between populations of neurons has been widely observed in the brain and is essential for neuronal computation. The different mechanisms by which reciprocal neuronal activity is generated remain to be established. A common motif in neuronal circuits is the presence of afferents that provide excitation to one set of principal neurons and, via interneurons, inhibition to a second set of principal neurons. This circuitry can be the substrate for generation of reciprocal signals. Here we demonstrate that this equivalent circuit in the cerebellar cortex enables the reciprocal firing rates of Purkinje cells to be efficiently generated from a common set of mossy fiber inputs. The activity of a mossy fiber is relayed to Purkinje cells positioned immediately above it by excitatory granule cells. The firing rates of these Purkinje cells increase as a linear function of mossy fiber, and thus granule cell, activity. In addition to exciting Purkinje cells positioned immediately above it, the activity of a mossy fiber is relayed to laterally positioned Purkinje cells by a disynaptic granule cell → molecular layer interneuron pathway. Here we show in acutely prepared cerebellar slices that the input-output relationship of these laterally positioned Purkinje cells is linear and reciprocal to the first set. A similar linear input-output relationship between decreases in Purkinje cell firing and strength of stimulation of laterally positioned granule cells was also observed in vivo. Use of interneurons to generate reciprocal firing rates may be a common mechanism by which the brain generates reciprocal signals.

scholarly journals Reductions in Hydrogen Sulfide Precede Onset of Mitochondrial Quality Control in the Corneal Kindled Mouse Model of Epilepsy

2021 ◽  
Author(s):  
Christi Cho ◽  
Maxwell Zeigler ◽  
Stephanie Mizuno ◽  
Richard S. Morrison ◽  
Rheem Totah ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Mouse Model ◽  
Membrane Integrity ◽  
Brain Homogenate ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Mitochondrial Stress ◽  
Acute Seizures ◽  
Related Proteins

Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S), a gasotransmitter, promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures and during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS subsequent to acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the corneal kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels in whole brain homogenate and expression of related genes in corneal kindled mice were not altered. However, plasma H2S and MeSH levels were significantly lower during kindling, but not after established kindling. Morever, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, Opa1, Mfn2, Drp1, and Mff during kindling, which did not correlate with gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.

Effects of Carbon Dioxide and Oxygen on Properties of Experimental Seizures in Mice

1955 ◽  
Vol 184 (1) ◽  
pp. 202-208 ◽  
Author(s):  
Dixon M. Woodbury ◽  
Lawrence T. Rollins ◽  
Joyce R. Henrie ◽  
Joseph C. Jones ◽  
Tada Sato
Keyword(s):  
Carbon Dioxide ◽  
Carbon Dioxide Concentration ◽  
Anticonvulsant Effect ◽  
Maximal Electroshock ◽  
Low Oxygen ◽  
Excitatory Effect ◽  
The Brain ◽  
Electroshock Seizures ◽  
Tonic Phase ◽  
Convulsant Dose

The influence of various concentrations of carbon dioxide and oxygen on the pattern of maximal electroshock seizures (MES), on pentylenetetrazol (Metrazol)-induced seizures, and on recovery time (RT50) from MES has been studied in mice. The major results are summarized as follows: Increasing the concentration of carbon dioxide in 20% oxygen resulted in marked changes in the MES pattern. The duration of the tonic flexor component was increased, and the duration of the tonic extensor component and of the entire tonic phase was decreased; the ratio of flexion to extension was increased markedly. These changes indicate an anticonvulsant effect of carbon dioxide. Carbon dioxide in a concentration of 15.6% protected 50% of mice against a 97% convulsant dose (CD97) of Metrazol. Hypoxia, induced by inhalation of 15 or 10% oxygen, decreased the duration of the tonic flexor component and increased the duration of the tonic extensor component of the MES; the duration of the entire tonic phase was increased; the ratio of flexion to extension was slightly decreased. These changes indicate an excitatory effect of low oxygen concentrations on the brain, under the stated conditions. Hyperoxia, induced by inhalation of 50, 75 or 90% oxygen, in contrast to hypoxia, resulted in effects on MES similar to those produced by inhalation of carbon dioxide. The RT50 was slightly, but not significantly, decreased by hypoxia (15% oxygen), unchanged by hyperoxia (50% oxygen), and markedly increased by an increase in carbon dioxide concentration. Carbon dioxide (5 and 10%) combined with hypoxia (10% oxygen) produced effects on MES pattern and RT50 similar to those produced by carbon dioxide in 20% oxygen.

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