**3. The endocannabinoid system and epilepsy**

phytocannabinoids found in the cannabis plant do offer some very unique anticonvulsant

In this chapter the authors will provide a brief review of epilepsy and epileptogenesis followed by a review of how the endocannabinoid system can alter the processes involved in the propagation and suppression of epileptic seizures. This is then followed by a review of the phytocannabinoids and their anticonvulsant mechanisms of action. Finally, the authors provide a historical background on the use of cannabis to treat patients with epilepsy and a

Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. It is defined as a disease of the brain in which the patient has either (1) two or more unprovoked seizures occurring more than 24 hours apart or (2) one unprovoked seizure and a probability of further seizures to be greater than 60% [1]. The prevalence of epilepsy worldwide is estimated to be between 4 and 10/1000 people with epilepsy accounting for up to 0.5% of the global burden of disease [2, 3]. There is significant geographic variation with prevalence rates of epilepsy

Most children and adults with epilepsy respond well to anticonvulsant therapy with approximately 50% of adults and 70% of children becoming seizure free with their first anticonvulsant medication [5, 6, 7]. Up to 30% of patients with epilepsy can be considered to be drug resistant which is defined by the International League Against Epilepsy as having failed two

In patients who have failed two appropriate anticonvulsants the likelihood of seizure freedom with the addition of further anticonvulsant therapies is low. Treatment options for patients with drug resistant epilepsy include further trials of anticonvulsants, resective surgery, neural pathway stimulation with receptive or vagal nerve stimulation and dietary therapies [10]. Further trials of anticonvulsants in adults will result in 16% of patients who had failed their first two medications becoming seizure free [11]. In pediatric patients while the likelihood of achieving remission for 1 year or more with further medication trials is higher at 57%, many will continue to have relapses over time [12]. Resective surgery success rates (as defined as obtaining Engel Class 1 seizure freedom) in pediatric and adult patients with surgically amenable epileptogenic lesions range from 34 to 90% depending on the nature and extent of the

A full review of the processes that result in brain abnormalities causing seizures (epileptogenesis) is beyond the scope of this chapter. However, in order to understand how cannabinoids can have potential in treating epilepsy it is worth knowing the basic principles of these processes. One of the major hallmarks of epilepsy is the presence of abnormal oscillatory events within neuronal networks in the form of recurrent interictal spikes and high frequency oscillations within the epileptic zones of the patients' brain [14]. These abnormal oscillations then

or more appropriate anticonvulsant treatments at an appropriate dosage [8, 9].

pharmacological properties that warrant further exploration.

prevalence rates being much higher in the developing world [4].

review of the most recent clinical trials.

202 Recent Advances in Cannabinoid Research

**2. Epilepsy**

lesion [10, 13].

The endocannabinoid system comprises the two endogenous endocannabinoid receptors (CB1R and CB2R) their two endogenously produced endocannabinoids; anandamide (*N*-arachidonyl-ethanolamide) and 2-AG (2-arachadonoylglycerol) which act as endogenous CBR ligands as well as the enzymes involved in endocannabinoid production and breakdown. Of the endocannabinoids produced in the human brain, 2-AG is produced in much higher concentrations and plays the most significant role in regulation of oscillatory networks [18]. For a full review of the endocannabinoid system please refer to this book's introduction and the review article by Ligresti et al. [19] CB1R is one of the most abundant G proteincoupled receptors (GPCR) within the mammalian brain and is expressed on the presynaptic axon terminal. In response to activation of the postsynaptic neuron, anandamide (a partial CB1R agonist) and 2-AG (a full CB1R agonist) are both produced within and released by the postsynaptic neuron. Activation of the presynaptic CB1R receptors by the endocannabinoids then results in a temporary suppression in voltage gated Ca2+ channels and activation of K+ channels resulting in suppression of further neurotransmitter release from the presynaptic neuron [20].

Although CB1R is one of the most abundantly expressed GPCRs in the brain, its expression is concentrated within certain groups of neurons. For example, in the hippocampus, CB1R expression is concentrated on the axon terminals of inhibitory GABAergic CA1 region interneurons and Schaffer collaterals arising from CA3 pyramidal cells [22]. These interneurons play a key role in the formation and maintenance of normal oscillatory behavior in the hippocampus essential for memory formation [18]. The effect of stimulation of CB1R is very localized within neuronal networks both from a spatial and temporal point of view. This is achieved by the production of monoacylglycerol lipase (MAGL) by astrocytes and nerve terminals which breaks down 2-AG in the synaptic cleft. This temporal and spatial control allows for precise regulation of oscillations within neuronal networks by the endocannabinoid system [18].

phytocannabinoids, they appear to display widely different effects on the mammalian central nervous system. The structural and stereochemical requirements for biological activity of the cannabinoids have been well established. Most biologically active cannabinoids (with a few

As well, naturally occurring cannabinoids are biologically active in the trans (−) enantiomer [24]. Following the first isolation of the cannabinoids it did not take long for their anticonvulsant properties to be recognized [25]. Of the cannabinoids produced by the *C. sativa* the most

such as anandamide. Through their activation of CB1R, anandamide and the synthetic cannabinoid WIN 55,212-2 were able to block the production of postsynaptic neuronal spiking and excitatory post synaptic potential production. Both compounds were also able to sup-

tion. Depletion of Mg2+ in solution allows activation of NMDA receptors at normal resting potentials without the usual prerequisite neuronal depolarization. This effect was abolished when CB1R antagonists were added, suggesting that the effect was secondary to activation

affinity partial agonist of both CB1R and CB2R that is competitive with both anandamide

both anticonvulsant and proconvulsant activity depending on the dosage, animal species and seizure model used. In Maximal Electroshock (MES) and Maximal Electroshock Threshold (MEST) mouse models which mimic generalized onset convulsive seizures both Δ9-THC and its metabolites showed anticonvulsant activity by blocking or increasing the latency to hind

trically induced after discharges at the site of electrode implantation in the left subiculum.

and proconvulsant effects in focal onset epilepsies [27]. In the cobalt model of focal epilepsy

of brief intermittent cortically recorded after discharges [27]. Similar findings were seen in a





of several anticonvulsants [28]. In models that showed an anticonvulsant effect of Δ<sup>9</sup>

of magnitude suggesting that much of the anticonvulsant activity attributed to Δ<sup>9</sup>

press the production of abnormal burst activity in neurons placed in Mg2

[19]. Numerous studies have assessed the anticonvulsant activity of Δ<sup>9</sup>

lites with conflicting results. These studies showed that Δ<sup>9</sup>

and an alkyl group on the C3













Cannabis for Pediatric and Adult Epilepsy http://dx.doi.org/10.5772/intechopen.85719

+


aromatic positions.


205

depleted solu-






exceptions) have a hydroxyl group on the C1

cannabidiol (CBD).

of CB1R by these agents [26]. Δ<sup>9</sup>

and 2-AG. The direct activation of CB1R by Δ<sup>9</sup>

limb extensor seizures [27]. In other studies Δ<sup>9</sup>

In a rat model of electrically induced limbic seizures Δ<sup>9</sup>

remote from the site of stimulation. This suggested that Δ<sup>9</sup>

rat model using iron to induce a seizure focus. While both Δ<sup>9</sup>

caused increased cortical excitability, only Δ<sup>9</sup>

three of its metabolites including 11-OH-Δ<sup>9</sup>

in fact come from its metabolites [27].

lesion. This was not seen with Δ<sup>9</sup>

vulsant effect of 11-OH-Δ<sup>9</sup>

However, Δ<sup>9</sup>

in rats Δ<sup>9</sup>

11-OH-Δ<sup>9</sup>

comprehensively studied in the field of epilepsy are Δ<sup>9</sup>

Initial research focused on the anticonvulsant effects of Δ<sup>9</sup>

During an epileptic seizure there is excessive glutamate release from presynaptic excitatory neurons. In rodent models of epilepsy this has been shown to cause increased production of both 2-AG and anandamide that in turn active CB1R on the glutamatergic axon terminals to decrease the release of further excessive glutamate. This prevents further neuronal hyperexcitability which may play a role in terminating seizures. The increased anandamide is felt to play a role in preventing seizure induced excitatory neurotoxic effects [18, 21].

Temporal lobe epilepsy secondary to mesial temporal sclerosis (scarring of the hippocampi) is a common cause of epilepsy in adults that is often amenable to surgical resection of the mesial temporal structures. Pathological examination of surgically resected specimens has shown alterations in expression of CB1R of neurons within the hippocampi that provide insight into how disruption of the endocannabinoid system could predispose to epileptogenesis. In resected hippocampi there is a downregulation of CB1R expression on the axon terminals of excitatory (glutamatergic) neurons within the inner molecular layer of the dentate gyrus and an upregulation of CB1R expression on inhibitory (GABAergic) axon terminals within the dentate molecular layer [18]. These changes in CB1R expression result in both a loss of the normal inhibition of excessive glutamate release and increased suppression of GABAergic activity both of which result in increased neuronal hyperexcitability and subsequent seizure generation [22]. In patients with chronic epilepsy, there is also a decrease in the amount of anandamide and 2-AG released with excessive neuronal activation further contributing to a loss of the endocannabinoid mediated inhibition of excessive neuronal activation [18].

The growing body of evidence demonstrating the role the endocannabinoid system plays in the brains' mechanisms in regulating neuronal network oscillations and preventing excessive neuronal hyperexcitability coupled with alterations in the endocannabinoid receptors seen in epileptogenic tissue make the endocannabinoid system an attractive therapeutic target in the treatment of epilepsy. Modulation of the endocannabinoid system would provide a potential novel anticonvulsant mechanism not provided by other anticonvulsant therapies.
