Evidence for decreased calcium dependent potassium conductance in hippocampal CA3 neurons of genetically epilepsy-prone rats

Verma-Ahuja, Suneeta; Evans, Marilyn; Pencek, T.L.

doi:10.1016/0920-1211(95)00040-2

Cited by 40 publications

(26 citation statements)

References 37 publications

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“…Earlier reports have demonstrated the important differences between CA1 and CA3 hippocampal cells, including the more homogeneous group of cells in CA3 than the CA1 pyramidal cell population, and the difference in neuronal excitability, especially the calcium dependent potentials in the CA1 and CA3 hippocampal cells [60,61], as well as the subtle changes in the slow afterhyperpolarization (AHP) in CA1 but a marked reduction in spike frequency adaptation accompanied by a significant reduction in AHP in CA3 in an epilepsy model [62]. Our study also suggested the differential excitability profile between CA1 and CA3.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. Methods: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1β levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 μg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 μg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1β levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. Results: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1β or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na⁺ current (I_Na), with a negative shift in the inactivation curve of I_Na and reduced the amplitude of APs along with decreased firing of APs. Conclusion: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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“…However, several lines of evidence lend credence to the idea that KCa2 channels may play a role in regulating seizure discharges and could therefore be a target for epilepsy drug treatment. Genetically epilepsy prone rats exhibit reduced afterhyperpolarization (AHP) currents resulting in a marked reduction in spike frequency adaptation in CA3 hippocampal neurons [42], and have more recently been found to express lower levels of KCa2.1 and KCa2.3 but higher levels of KCa2.2 in inferior colliculus neurons [43], suggesting that KCa2 channel dysregulation may contribute to the seizure susceptibility of these animals. It has further been shown that rats rendered chronically epileptic as a result of pilocarpineinduced status epilepticus exhibit significantly reduced KCa2-mediated AHP currents in CA1 hippocampal neurons [44].…”

Section: +mentioning

confidence: 99%

The Riluzole Derivative 2-Amino-6-trifluoromethylthio-benzothiazole (SKA-19), a Mixed KCa2 Activator and NaV Blocker, is a Potent Novel Anticonvulsant

et al. 2015

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Inhibitors of voltage-gated sodium channels (Na v ) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent Na V channel blocker and an activator of small-conductance Ca 2+ -activated K + channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED 50 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED 50 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED 50 12.2 mg/kg), Frings audiogenic seizuresusceptible mice (ED 50 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED 50 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD 50 /ED 50 ) of 6-9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects Na V and KCa2 channels, except that SKA-19 has a~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channelactivating and Na v channel-blocking activity exert broadspectrum anticonvulsant and analgesic effects.

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“…The genetically epilepsy-prone rat (GEPR), an audiogenic strain similar to Wistar audiogenic rats, exhibited reduced sensitivity to exogenous GABA in auditory brainstem circuits (33). In addition, electrophysiological studies of hippocampal slices from adult GEPR rats suggest several features leading to increased excitability, including a reduced GABA A -mediated inhibition, increased input impedance, reduced spike frequency adaptation, and increased paired-pulse facilitation (34)(35)(36). Interestingly, these investigators have reported significant differences in the cellular alterations observed in the CA1 and CA3 regions of the GEPR hippocampus, indicating that epileptic hyperactivity at the cellular level may be highly dependent on the specific brain region examined.…”

Section: Discussionmentioning

confidence: 99%

Reduced hippocampal GABAergic function in Wistar audiogenic rats

Drumond

Kushmerick

Guidine

et al. 2011

Braz J Med Biol Res

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Evidence for decreased calcium dependent potassium conductance in hippocampal CA3 neurons of genetically epilepsy-prone rats

Cited by 40 publications

References 37 publications

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

The Riluzole Derivative 2-Amino-6-trifluoromethylthio-benzothiazole (SKA-19), a Mixed KCa2 Activator and NaV Blocker, is a Potent Novel Anticonvulsant

Reduced hippocampal GABAergic function in Wistar audiogenic rats

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