Pursuing paradoxical proconvulsant prophylaxis for epileptogenesis

Abstract

There are essentially two potential treatment options for any acquired disorder: symptomatic or prophylactic. For acquired epilepsies that follow a variety of different brain insults, there remains a complete lack of prophylactic treatment options, whereas at the same time these epilepsies are notoriously resistant, once they have emerged, to symptomatic treatments with antiepileptic drugs. The development of prophylactic strategies is logistically challenging, both for basic researchers and clinicians. Nevertheless, cannabinoid-targeting drugs provide a very interesting example of a system within the central nervous system (CNS) that can have very different acute and long-term effects on hyperexcitability and seizures. In this review, we outline research on cannabinoids suggesting that although cannabinoid antagonists are acutely proconvulsant, they may have beneficial effects on long-term hyperexcitability following brain insults of multiple etiologies, making them promising candidates for further investigation as prophylactics against acquired epilepsy. We then discuss some of the implications of this finding on future attempts at prophylactic treatments, specifically, the very short window within which prevention may be possible, the possibility that traditional anticonvulsants may interfere with prophylactic strategies, and the importance of moving beyond anticonvulsants-even to proconvulsants-to find the ideal preventative strategy for acquired epilepsy.

Figure 1. Cannabinoid-targeting molecules

Chemical structures of select cannabinoid-targeting molecules described in the text (Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience, (Piomelli, 2003), copyright 2003). A. An exogenous cannabinoid agonist, Δ⁹-tetrahydrocannabinol (THC), the active ingredient found in the psychoactive drug, marijuana B. An endogenous cannabinoid, 2-arachindonoylglycerol (2-AG), one of the major endocannabinoids found in the CNS C. An exogenous CB₁ receptor antagonist, SR141716A (Rimonabant), the first CB₁ antagonist to be used clinically.

Figure 2. Basic Schematic of Depolarization-Induced Suppression of Inhibitory Transmission by Cannabinoids

Schematic of depolarization-induced suppression of inhibition (DSI). GABA (brown dots) release from the presynaptic (green-blue) cell is suppressed by postsynaptic depolarization. Depolarization of the postsynaptic (purple) cell leads to calcium entry, activating the production and release of endocannabinoids (green hexagons). Endocannabinoids activate CB1 receptors (pink receptor) on the presynaptic cell, which are G-protein coupled and ultimately decrease Ca²⁺ entry into the presynaptic bouton, thus decreasing the release of transmitter from the presynaptic cell. (inset) Evoked IPSPs generated by GABA release are reduced by postsynaptic depolarization, while in the presence of the CB1 antagonist, SR141716A (SR), postsynaptic depolarization has no effect on evoked IPSPs. A similar process can occur at excitatory synapses to generate depolarization-induced suppression of excitation (see ‘Essentials of Cannabinoid Signaling’ in text).

Figure 3. Acute effects of cannabinoids on seizures

(Modified with permission from Wallace et al., 2003. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. The Journal of Pharmacology and Experimental Therapeutics Online. URL: http://www.jpet.aspetjournals.org/.) Cannabinoid levels are increased in the brain after seizures, and cannabinoid agonists are acutely anticonvulsant, whereas antagonists are proconvulsant in already epileptic animals. A. A CB1 agonist, (+) WIN blocks acute seizures in epileptic animals. B. Endogenous 2-AG levels are increased by seizures. C. A CB1 antagonist, SR141716A (SR) is proconvulsant in epileptic but not in control animals

Figure 4. SR141716A (SR), an acute proconvulsant in already hyperexcitable animals, blocks the emergence of increased seizure susceptibility in the hyperthermia-induced prolonged febrile seizure model of epileptogenesis

(Modified with permission from Chen et al., 2007. J Neurosci.) Animals exposed to prolonged hyperthermic seizures (HT) early in life have an increased susceptibility to kainate challenge later in life compared to control animals not exposed to hyperthermia. This increased susceptibility is abolished in animals treated with SR at the time of prolonged febrile seizures (1 mg/kg). A. Representative traces from hippocampal depth EEG recordings at baseline and 10 min after injection of kainate (5 mg/kg). B. Latency to first seizure is significantly decreased in animals exposed to hyperthermia (HT + vehicle), but this decrease is prevented by SR at the time of insult (HT + SR). C. SR injection at the time of initial insult also prevents the increase in total seizure time seen after HT.