Anticonvulsant activity of gap-junctional blocker carbenoxolone in albino rats

Suneel Kumar Reddy, Navin A. Patil, Vinod Nayak, Smita Shenoy, Anoosha Bhandarkar, Shankar M. Bakkannavar, Rahul Kotian


Background: Gap junctions (GJs) are clusters of channels that connect the interiors of adjoining neurons and mediate electrical/electrotonic coupling by transfer of ions and small molecules. Electrotonic coupling between principal neurons via GJs is increasingly recognized as one of the mechanisms in the pathogenesis of the abnormal neuronal synchrony that occurs during seizures. Carbenoxolone the succinyl ester of glycyrrhetinic acid obtained from liquorice has been shown to have the property of blocking gap junctional intercellular communication. The objectives were to study if carbenoxolone has in-vivo anticonvulsive activity in pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure models and to probe the functional role of GJs in seizures.

Methods: Carbenoxolone was tested for anticonvulsive effect in albino rats subjected to seizures by the PTZ and MES at three doses 100 m/kg, 200 m/kg, 300 m/kg. In the PTZ model parameters observed were seizure protection, seizure latency and seizure duration. In the MES model parameters observed were seizure protection and seizure duration.

Results: The results showed that the carbenoxolone has anticonvulsant activity in both PTZ and MES induced seizures with better protection in the PTZ induced seizures. In the PTZ model carbenoxolone produced a statistically significant increase in seizure latency, decrease in seizure duration and seizure protection. In the MES model carbenoxolone produced a statistically significant decrease in seizure duration.

Conclusions: Carbenoxolone has in-vivo anticonvulsive effect and could be useful in both petitmal (absence) seizures and grand mal (generalized tonic-clonic epilepsy) seizures. The protective effect of carbenoxolone could be due to blockade of GJ channels that mediate electro tonic coupling and thereby prevent the neural synchronization that is characteristic of seizures. The study also supports the view that GJs have a functional role in the electrophysiology of seizures and GJ blockers have potential as a new class of antiepileptic drugs.


Carbenoxolone, Gap junctions, Anticonvulsant

Full Text:



Ganong WF. Synaptic and junctional transmission. In: Review of Medical Physiology. 22nd Edition. Boston: McGraw Hill; 2005: 85.

Dudek FE. Gap junctions and fast oscillations: a role in seizures and epileptogenesis? Epilepsy Curr. 2002;2(4):133-36.

Carlen PL, Skinner F, Zhang L, Naus C, Kushnir M, Perez Velazquez JL. The role of gap junctions in seizures. Brain Res Brain Res Rev. 2000;32(1):235-41.

Gigout S, Louvel J, Pumain R. Effects in vitro and in vivo of a gap junction blocker on epileptiform activities in a genetic model of absence epilepsy. Epilepsy Res. 2006;69(1):15-29.

Davidson JS, Baumgarten IM. Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communication. Structure-activity relationships. J Pharmacol Exp Ther. 1988;246(3):1104-7.

Jackson H. On the anatomical, physiological and pathological investigation of epilepsies. West Riding Lunatic Ssylum Med Rep 1873;3:315.

Taylor J. Selected Writings of John Hughlings Jackson. London: Hadder and Stoughton; 1931:90-111.

Bennett MV, Zukin RS. Electrical coupling and neuronal synchronization in the Mammalian brain. Neuron. 2004;41(4):495-511.

Traub RD, Whittington MA, Buhl EH, LeBeau FE, Bibbig A, Boyd S, et al. A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures. Epilepsia. 2001;42(2):153-70.

Perez Velazquez JL, Carlen PL. Gap junctions, synchrony and seizures. Trends Neurosci. 2000;23(2):68-74.

Perez-Velazquez JL, Valiante TA, Carlen PL. Modulation of gap junctional mechanisms during calcium-free induced field burst activity: a possible role for electrotonic coupling in epileptogenesis. J Neurosci. 1994;14(7):4308-17.

Szente M, Gajda Z, Said Ali K, Hermesz E. Involvement of electrical coupling in the in vivo ictal epileptiform activity induced by 4-aminopyridine in the neocortex. Neuroscience. 2002;115(4):1067-78.

Jahromi SS, Wentlandt K, Piran S, Carlen PL. Anticonvulsant actions of gap junctional blockers in an in vitro seizure model. J Neurophysiol. 2002;88(4):1893-902.

Tripathi KD. In: Essentials of Medical Pharmacology. 5th Edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2003: 597.

Sweetman SC. Martindale: the Complete Drug Reference. 34th Edition. London: Pharmaceutical Press; 2005: 1254.

Schmidt D, Rogawski MA. New strategies for the identification of drugs to prevent the development or progression of epilepsy. Epilepsy Res. 2002;50(1-2):71-8.

Hosseinzadeh H, Nassiri Asl M. Anticonvulsant, sedative and muscle relaxant effects of carbenoxolone in mice. BMC Pharmacol. 2003;3:3.

Ambavade SD, Kusture VS, Kasture SB. Anticonvulsant activity of roots and rhizomes of Gyycyrrhiza glabra. Indian J Pharmacol. 2002;34:251-5.

Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: ii. Anticonvulsant drug screening. Epilepsia. 1978;19(4):409-28.

Jefferys JG, Haas HL. Synchronized bursting of CA1 hippocampal pyramidal cells in the absence of synaptic transmission. Nature. 1982;300(5891):448-50.

Taylor CP, Dudek FE. Synchronous neural afterdischarges in rat hippocampal slices without active chemical synapses. Science. 1982;218(4574):810-2.

Gajda Z, Gyengési E, Hermesz E, Ali KS, Szente M. Involvement of gap junctions in the manifestation and control of the duration of seizures in rats in vivo. Epilepsia. 2003;44(12):1596-600.

Gigout S, Louvel J, Kawasaki H, D’Antuono M, Armand V, Kurcewicz I, et al. Effects of gap junction blockers on human neocortical synchronization. Neurobiol Dis. 2006;22(3):496-508.

Traub RD, Draguhn A, Whittington MA, Baldeweg T, Bibbig A, Buhl EH, et al. Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis. Rev Neurosci. 2002;13(1):1-30.

Ross FM, Gwyn P, Spanswick D, Davies SN. Carbenoxolone depresses spontaneous epileptiform activity in the CA1 region of rat hippocampal slices. Neuroscience. 2000;100(4):789-96.