How cannabinoids reduce neuronal excitability is not exactly known but the following options are possible:
- Neuronal activity induces a Cl- influx through 2AG/Anandamide and CB2 (den Boon et al., 2014).
- Anandamide reduces burst-firing in neurons (Evans et al., 2008).
- cannabinoids reduce the number of neurotransmitter vesicles available for fusion (García-Morales et al., 2015).
So far, the only cannabinoids proven to be effective against epilepsy in clinical trials are CBD and THC (see below), but other cannabinoids like CBDV and THCV are likely to follow. In rats, THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011).
Similarly, CB1 activation decreases synchrony in cortical neurons (Sales-Carbonell et al., 2013) suggesting THC (like substances) can be used to suppress seizures. In healthy human volunteers, 10 mg oral THCV reduced functional network connectivity in the brain (measured by fMRI)(Rzepa et al., 2015). Although this does not prove anything in itself, it does support the idea that cannabinoids can reduce network synchronization. In heterologous cells (HEK293), THC and CBD were found to inhibit T-type calcium channels with an IC50 of approximately 1μM (Ross et al., 2008). THC-mediated inhibition was frequency dependent where CBD-mediated inhibition was not.
THCV significantly reduced epilepsy seizure incidence starting with doses of 0.25 mg/kg in animal models. THCV shows antiepileptiform and anticonvulsant properties, probably related to its activity in CB1 receptors (Gaston & Friedman, 2017; Hill et al., 2010).
CBDV, as well as CBD, have a huge potential to treat epilepsy (Gaston & Friedman, 2017; Rosenberg, Patra, & Whalley, 2017, Wallace et al., 2001). CBDV showed anticonvulsant properties in three different models of seizure, with additive effects when it was co-administered with CBD. Anticonvulsant properties of CBDV were not CB1 mediated (Hill et al., 2013). In vitro studies also support the anti-epileptic properties of CBDV (Amada, Yamasaki, Williams, & Whalley, 2013; A. J. Hill et al., 2012).
As T-type calcium channels function in thalamus-mediated synchronization of brain regions and are implicated in various types of epilepsy, THC and CBD are likely to suppress seizure generation. In human neuroblastoma cells (SH-SY5Y) and mouse cortical neurons CBD and CBG both blocked sodium channels Nav1.1, 1.2 and 1.5 (Hill et al., 2014). Interestingly, CBD but not CBG protected against pentyleneterzole (PTZ)-induced seizures in rat, suggesting that the anti-convulsant effect of CBD is not just through blocking sodium channels. Interestingly, cannabis was also shown to prevent the development of seizures/epilepsy (Brust et al., 1992), suggesting a prophylactic effect of cannabinoids. In mice, stimulating CB1 receptors (ACEA) or blocking TRPV1 receptors (capsazepine) protected against PTZ-induced seizures (Naderi et al., 2015). Interestingly, co-administration of both compounds attenuated the anti-convulsive effect, suggesting an interaction between CB1 and TRPV1 mediated signaling. In rats, the synthetic CB1 agonist WIN 55-212-2 was protective against the development of epilepsy when administered after an episode of status epilepticus (induced by pilocarpine)(Di Maio et al., 2014).
Cultured HEK293 cells carrying human epilepsy-associated mutations in Nav1.6 display increased resurgent sodium currents and increased excitability. 1 μM CBD reduced resurgent sodium currents and increased the refractory period. In cultured mouse striatal neurons CBD reduced overall action potential firing suggesting therapeutic potential (Patel et al., 2016).
Sub-acute treatment with WIN 55-212-2 for 15 days dramatically reduced the frequency of spontaneous seizures, their duration and intensity and the incidence of neuronal oxidative damage. In rats, WIN 55-212-2 delayed the onset of audiogenic epilepsy by two weeks suggesting a preventive effect of Cannabinoid on the development of epilepsy as well as a curative effect (Vinogradova and van Rijn, 2015).
In a mouse model of epilepsy (Maximal Electro Shock), the following cannabinoids were found to be anti-convulsive (ED50)(Devinsky et al., 2014): CBD 120 mg/kg Δ9THC 100 mg/kg 11-OH-Δ9THC 14 mg/kg 8β-OH-Δ9THC 100 mg/kg Δ9THCA 200-400 mg/kg Δ8THC 80 mg/kg CBN 230 mg/kg Δ9α/β-OH-hexahydro-CBN 100 mg/kg Apart from that the doses reported above are incredibly high, it does provide a proof of principle that many cannabinoids exert anti-convulsive effects.
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