Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder

Abstract

Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD's antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids' pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid's potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid's therapeutic potential for CDD.

Keywords: CBD; CDD; CDKL5; cannabidiol; cannabinoids; refractory epilepsy.

Figure 1

Schematic of the Endocannabinoid System at the Synapses in the Cerebral Cortex. The endogenous Endocannabinoids AEA and 2-AG act as retrograde neurotransmitters that activate CB1R. Presynaptic CB1R activation leads to GIRK channel opening, promoting K⁺ efflux, hyperpolarizing the presynaptic membrane, and reducing neuronal excitability by simultaneously preventing the release of the excitatory neurotransmitter glutamate and promoting the release of the inhibitory neurotransmitter GABA. CB1R activation also inhibits some VGCCs, reducing Ca²⁺ influx. Since Ca²⁺ is required for neurotransmitter release into the synaptic cleft, this results in an overall inhibitory effect on synaptic transmission. 5-HT1A receptors also activate GIRKs and inhibit VGCC response to stimulation by CBD, also reducing neuronal excitability. Additionally, 5-HT1A modulates presynaptic vesicle release by inhibiting the adenylyl cyclase pathway, further dampening neuronal transmission. TRPV1, a non-selective cation channel, is activated by the endocannabinoids AEA, CBD, and THC. However, prolonged exposure to plant-derived phytocannabinoids desensitizes TRPV1, preventing activation by endogenous ligands. In both the pre- and postsynaptic regions, TRPV1 enhances neuronal excitability through Ca²⁺ influx and depolarization of the neuronal membrane. Therefore, CBD has an overall inhibitory effect on synaptic transmission. AMPA-R are ion channels responsible for the majority of fast excitatory neurotransmission in the brain. The binding of glutamate to AMPA-R on the postsynaptic membrane leads to Na⁺ influx and depolarization. CBD inhibits FAAH, the enzyme responsible for AEA breakdown, leading to AEA accumulation in the synaptic cleft and enhancing its inhibitory effects. Additionally, CBD interacts with the adenosine system by preventing adenosine reuptake, which enhances neuronal inhibition via GIRK activation and inhibition of VGCC and adenylyl cyclase pathways. GABA_AR is the primary target of GABA. As a Cl⁻ channel, its activation by GABA results in postsynaptic membrane hyperpolarization, inhibiting neuronal excitability. Conversely, the excitatory neurotransmitter glutamate binds to NMDA-R, depolarizing the postsynaptic membrane and increasing neuronal excitability. Abbreviations: Receptors; CB1R (Cannabinoid Receptor 1), GIRK (G-protein-coupled inwardly rectifying potassium), VGCC (Voltage-Gated Calcium Channel), TRPV1 (transient receptor potential cation channel subfamily V member 1), GPR55 (G protein-coupled receptor 55), AMPA-R (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), NMDA-R (N-methyl-D-aspartate Receptor), GABA_AR (γ-aminobutyric acid Receptor A), FAAH (Fatty acid amide hydrolase), 5-HT1A (5-hydroxytryptamine 1A Receptor), Endocannabinoids; AEA (Anandamide), 2-AG (2-Arachidonoylglycerol), Phytocannabinoids; THC (Δ9-tetrahydrocannabinol), CBD (Cannabidiol), Neurotransmitters; GABA (γ-aminobutyric acid), Glut (Glutamate). Created in BioRender [54].

Figure 2

Schematic of CDKL5 interactions on cannabinoid targets. NMDA-R mediates the translocation of CDKL5 to the cytoplasm via PP1, which promotes CDKL5 degradation by accumulation in the cytoplasm. CDKL5 also regulates the localization of NMDA-R and AMPA-R by promoting their removal from the postsynaptic membrane. Cav2.3 is a voltage-gated calcium channel important for depolarization of the postsynaptic membrane. The resultant Ca²⁺ also positively affects NMDA-R. CDKL5 downregulates Cav2.3 by direct phosphorylation. CB1R, TRPV1, and TRPV2 levels are affected in cdkl5^−/y KO mice; however, the mechanism is tissue-specific and still unknown. Abbreviations: Receptors: CB1R (Cannabinoid Receptor 1), VGCC (Voltage-Gated Calcium Channel), TRPV1 (transient receptor potential cation channel subfamily V member 1), TRPV1 (transient receptor potential cation channel subfamily V member 2), GPR55 (G protein-coupled receptor 55), AMPA-R (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), NMDA-R (N-methyl-D-aspartate Receptor), GABA_AR (γ-aminobutyric acid Receptor A) Neurotransmitters: GABA (γ-aminobutyric acid), Glut (Glutamate). Created in BioRender [68].