Approximately 50 million people worldwide are chronically affected by epilepsyia serious neurological disorder typically manifesting as spontaneous convulsions and/or a loss of consciousness. Epilepsy carries long term health implications such as cognitive deficits, mental health problems and physical (sclerotic) damage to affected areas, particularly in children. Epilepsy symptoms are caused by the appearance of abnormal electrical seizure discharges and are characterised by episodic high frequency neuronal firing within various brain areas. Seizures are frequently a result of excitatory and inhibitory synaptic imbalances and usually begin (and may remain confined) to a specific area and/or spread to other regions of the brain. The specific cellular, molecular and genetic mechanisms underlying the many forms of this disorder are still poorly understood, particularly in the infant, paediatric and juvenile populations where it is most prevalent (10.5m global casesii) and may vary significantly from individual to individual. Furthermore, anticonvulsant therapies are associated with significant cognitive side-effects, toxicity, unknown effects on brain development and a serious lack of seizure control at therapeutic dosesiii. The development of both in vitro and in vivo animal models of epilepsy permits the reproduction of specific seizure discharge features seen in human clinical cases, allows for a better understanding of the disease state and aids the development and screening of more effective anticonvulsant agents.
CB1 receptors (activated by D9-THC or the principal endogenous endocannabinoids, 2-arachidonoyl glycerol (2-AG) and anandamide), are found in many mammalian neuronesiv, which strongly supports a role for endocannabinergic transmission in higher brain functions. In the CNS, the endogenous CB1 receptor ligands, anandamide and 2-AG typically act in a retrograde (presynaptic site of action) neuromodulatory manner, the release of which is mediated via two distinct pathways; calcium entry following neurone depolarisation, and metabotropic glutamate receptor (mGluR) activation. The CB1 receptor also modulates postsynaptic membrane conductances which are thought to be a result of the CB1 dependent modulation of intracellular cAMP levels. Additionally, anandamide has postsynaptic ion channel effects, mediated independently of CB1 or CB2 receptors and, of considerable relevance to epilepsy, has been shown to modulate both fast (gamma) and slow (theta) rhythmic, oscillatory firingiv. It is clear that existing links between cannabinoids/endocannabinergic transmission, epilepsy and development present a compelling case for a detailed investigation of cannabinoids in immature in vitro models of epilepsy.
GW is currently investigating the potential for cannabinoids as anti-epileptic treatments in collaboration with Otsuka. This research is being conducted in partnership with researchers at the University of Reading. One of the techniques used by the team is to examine the antiepileptiform potential of cannabinoids using in vitro multielectrode array (MEA) extracellular electrophysiologic techniques on brain slices. A low magnesium ion saline solution or a 4AP (4-aminopyridine; a pro-convulsant) containing medium can trigger burst discharges that are synchronised throughout large cell populations in hippocampal or periform cortical slice cultures. These appear essentially identical to those evoked in vivo. By studying the impact of cannabinoid addition on the amplitude of the epileptiforms produced, researchers are able to recognise if our compounds could perform as an anti-epileptic drug in vivo.
Contributing author: Dr. Ben Whalley
iii. Suchomelova, L., Baldwin, R.A., Kubova, H., Thompson, K.W., Sankar, R. & Wasterlain, C.G. (2006). Treatment of experimental status epilepticus in immature rats: dissociation between anticonvulsant and antiepileptogenic effects. Pediatr Res, 59, 237-43.
iv. Hajos, N., Katona, I., Naiem, S.S., MacKie, K., Ledent, C., Mody, I. & Freund, T.F. (2000). Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. European Journal of Neuroscience, 12, 3239-3249.