The common features of all types of epilepsy are the synchronized and uncontrolled discharges of nerve cell assemblies. The reason for the pathologically synchronized discharges of the neuron is not exactly known yet. Recent reports claim that gap junctions have a critical role in neuronal synchronization. The present study was planned to investigate the effects of octanol, a gap junction blocker, on penicillin-induced experimental epilepsy. Permanent screw electrodes allowing EEG monitoring from conscious animals and permanent cannula providing the administration of the substances to the brain ventricle were placed into the cranium of rats under general anesthesia. After the postoperative recovery period, epileptiform activity was generated by injecting 300 IU crystallized penicillin through the ventricular cannula. When epileptiform activity, monitored from a digital recording system, reached at its maximum intensity, octanol was applied in the same way as penicillin administered. Application of octanol caused an inhibition in the epileptiform activity. Vehicle solution alone did not affect the epileptiform activity. Results of this study suggest that the blockade of electrical synapses may contribute to the prevention and amelioration of epileptic activity. Production of gap junction blockers selective for connexin types is needed. Further studies on the differential roles of gap junctions on certain epileptiform activities are required.
"Using fluorescence recovery after photobleaching increased GJ coupling was found in astrocytes cultured from human epileptic specimens when compared with cultures from non-epileptic tissue (Lee et al., 1995). Another strategy to investigate the role of the astrocytic syncytium in epilepsy is pharmacological disruption of GJ communication using inhibitors (such as carbenoxolone, halothan and octanol), substances producing intracellular acidification (sodium propionate, carbon dioxide) or Cx mimetic peptides (small peptides mimicking a sequence of the connexin subunit, inhibiting GJ and Cx hemichannels by binding to their extracellular domain) (Bostanci and Bagirici, 2006, 2007; Gajda et al., 2003; Gigout et al., 2006; Jahromi et al., 2002; Kohling et al., 2001; Medina-Ceja et al., 2008; Perez-Velazquez et al., 1994; Ross et al., 2000; Samoilova et al., 2003, 2008; Szente et al., 2002; Voss et al., 2009). Most of these studies reported antiepileptic effects of GJ blockade although proepileptic effects have also been observed (Voss et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Since astrocytes may sense and respond to neuronal activity these cells are now considered important players in brain signalling. Astrocytes form large gap junction coupled syncytia allowing them to clear the extracellular space from K(+) and neurotransmitters accumulating during neuronal activity, and redistribute it to sites of lower extracellular concentrations. Increasing evidence suggests a crucial role for dysfunctional astrocytes in the etiology of epilepsy. Notably, alterations in expression, localization and function of astroglial K(+) channels as well as impaired K(+) buffering was observed in specimens from patients with pharmacoresistant temporal lobe epilepsy and in chronic epilepsy models. Altered astroglial gap junction coupling has also been reported in epileptic tissue which, however, seems to play a dual role: i) junctional coupling counteracts hyperactivity by facilitating clearance of elevated extracellular K(+) and glutamate while ii) it also provides a pathway for energetic substrates and fuels neuronal activity. Dysfunctional astrocytes should be considered promising targets for new therapeutic strategies.
Neurochemistry International 01/2013; 63(7). DOI:10.1016/j.neuint.2013.01.011 · 3.09 Impact Factor
"In vivo seizure models, where cell-to-cell communication via gap junctions is manipulated before the administration of proconvulsant drugs, have suggested roles for gap junctional intercellular communication in ictogenesis acting via axonal excitatoryexcitatory gap junctions (Traub, et al. 2002). Gap junction blockade with both octanol and carbenoxolone has been shown to be protective against penicillin-induced ictogenesis in an in vivo rat seizure model (Bostanci and Bagirici 2006). Using a pentylenetetrazol (PTZ) seizure model, Nassiri-Asl and co-workers found that Cx36 gap junction blockade with quinine increased seizure latency and decreased seizure severity. "
[Show abstract][Hide abstract] ABSTRACT: Large-scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions. To explore roles for connexin36 (Cx36) gap junctions in seizures, we examined the seizure threshold of connexin36 knockout (Cx36KO) mice using a pentylenetetrazol (PTZ) model.
Mice (2-3months old) with Cx36 wildtype (WT) or Cx36KO genotype were treated with vehicle or 10-40mg/kg of the convulsant PTZ by intraperitoneal injection. Seizure and seizure-like behaviors were scored by examination of video collected for 20min. Quantitative real-time PCR (QPCR) was performed to measure potential compensatory neuronal connexin (Cx30.2, Cx37, Cx43 and Cx45), pannexin (PANX1 and PANX2) and gamma-aminobutyric acid type A (GABA(A)) receptor α1 subunit gene expression.
Cx36KO animals exhibited considerably more severe seizures; 40mg/kg of PTZ caused severe generalized (≥grade III) seizures in 78% of KO, but just 5% of WT mice. A lower dose of PTZ (20mg/kg) induced grade II seizure-like behaviors in 40% KO vs. 0% of WT animals. There was no significant difference in either connexin, pannexin or GABA(A) α1 gene expression between WT and KO animals.
Increased sensitivity of Cx36KO animals to PTZ-induced seizure suggests that Cx36 gap junctional communication functions as a physiological anti-convulsant mechanism, and identifies the Cx36 gap junction as a potential therapeutic target in epilepsy.
Brain research 11/2010; 1360:198-204. DOI:10.1016/j.brainres.2010.09.006 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epilepsy is an important problem in neurological disorders. The common features of all types of epilepsy are the synchronized and uncontrolled discharges of nerve cell assemblies. Recent studies claimed that gap junctions have a critical role in epileptic neuronal events. The aim of present study is to investigate the effects of connexin36 (Cx36) channel blocker quinine on penicillin-induced experimental epilepsy. For this purpose, 4 months old male Wistar rats were used in the present study. Permanent screw electrodes allowing EEG monitoring from conscious animals and permanent cannula providing the administration of the substances to the brain ventricle were placed into the cranium of rats under general anesthesia. At the end of the postoperative recovery period, epileptiform activity was generated by injecting 300 IU crystallized penicillin through the ventricular cannula. When the epileptiform activity, monitored from a digital recording system, reached maximal frequency and amplitude, quinine (200, 400 or 1000 nmol) was administered similar to penicillin. Effects of quinine on epileptiform activity were assessed by both electrophysiological and behavioral analysis. Quinine suppressed epileptiform activity by decreasing the amplitude and frequency of epileptiform spikes and by attenuating the epileptiform behavior. The outcomes of this study suggest that the blockade of Cx36 channels may contribute to the amelioration of epileptic activity.
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