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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Oct 16

PMID 39409097

Authors

Sean Massey

Anita Quigley

Simone Rochfort

John Christodoulou

Nicole J Van Bergen

Affiliations

Soon will be listed here.

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.

References

Vandrey R, Raber J, Raber M, Douglass B, Miller C, Bonn-Miller M . Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. JAMA. 2015; 313(24):2491-3. DOI: 10.1001/jama.2015.6613. View

Anderson L, Ametovski A, Luo J, Everett-Morgan D, McGregor I, Banister S . Cannabichromene, Related Phytocannabinoids, and 5-Fluoro-cannabichromene Have Anticonvulsant Properties in a Mouse Model of Dravet Syndrome. ACS Chem Neurosci. 2021; 12(2):330-339. DOI: 10.1021/acschemneuro.0c00677. View

Thornton C, Dickson K, Carty D, Ashpole N, Willett K . Cannabis constituents reduce seizure behavior in chemically-induced and scn1a-mutant zebrafish. Epilepsy Behav. 2020; 110:107152. PMC: 8276876. DOI: 10.1016/j.yebeh.2020.107152. View

Gray R, Whalley B . The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord. 2020; 22(S1):10-15. DOI: 10.1684/epd.2020.1135. View

Fehr S, Wong K, Chin R, Williams S, de Klerk N, Forbes D . Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology. 2016; 87(21):2206-2213. DOI: 10.1212/WNL.0000000000003352. View

Sun Y, Dolmetsch R . Investigating the Therapeutic Mechanism of Cannabidiol in a Human Induced Pluripotent Stem Cell (iPSC)-Based Model of Dravet Syndrome. Cold Spring Harb Symp Quant Biol. 2019; 83:185-191. DOI: 10.1101/sqb.2018.83.038174. View

Hill A, Weston S, Jones N, Smith I, Bevan S, Williamson E . Δ⁹-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia. 2010; 51(8):1522-32. DOI: 10.1111/j.1528-1167.2010.02523.x. View

Devinsky O, Verducci C, Thiele E, Laux L, Patel A, Filloux F . Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018; 86:131-137. DOI: 10.1016/j.yebeh.2018.05.013. View

Pasca A, Sloan S, Clarke L, Tian Y, Makinson C, Huber N . Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015; 12(7):671-8. PMC: 4489980. DOI: 10.1038/nmeth.3415. View

10.

Hodge R, Bakken T, Miller J, Smith K, Barkan E, Graybuck L . Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019; 573(7772):61-68. PMC: 6919571. DOI: 10.1038/s41586-019-1506-7. View

11.

Santos A, Nader G, El Sabbagh D, Urban K, Attisano L, Carlen P . Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation. Cells. 2023; 12(15). PMC: 10416870. DOI: 10.3390/cells12151949. View

12.

Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B . Key clinical features to identify girls with CDKL5 mutations. Brain. 2008; 131(Pt 10):2647-61. DOI: 10.1093/brain/awn197. View

13.

De Petrocellis L, Ligresti A, Moriello A, Allara M, Bisogno T, Petrosino S . Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2010; 163(7):1479-94. PMC: 3165957. DOI: 10.1111/j.1476-5381.2010.01166.x. View

14.

Whalley B, Lin H, Bell L, Hill T, Patel A, Gray R . Species-specific susceptibility to cannabis-induced convulsions. Br J Pharmacol. 2018; 176(10):1506-1523. PMC: 6487554. DOI: 10.1111/bph.14165. View

15.

Muller A, Helbig I, Jansen C, Bast T, Guerrini R, Jahn J . Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy. Eur J Paediatr Neurol. 2015; 20(1):147-51. DOI: 10.1016/j.ejpn.2015.09.001. View

16.

De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini P, Orlando P . Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008; 325(3):1007-15. DOI: 10.1124/jpet.107.134809. View

17.

Bakas T, van Nieuwenhuijzen P, Devenish S, McGregor I, Arnold J, Chebib M . The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABA receptors. Pharmacol Res. 2017; 119:358-370. DOI: 10.1016/j.phrs.2017.02.022. View

18.

Gallop K, Lloyd A, Olt J, Marshall J . Impact of developmental and epileptic encephalopathies on caregivers: A literature review. Epilepsy Behav. 2021; 124:108324. DOI: 10.1016/j.yebeh.2021.108324. View

19.

La Montanara P, Hervera A, Baltussen L, Hutson T, Palmisano I, De Virgiliis F . Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models. Sci Transl Med. 2020; 12(551). PMC: 7116442. DOI: 10.1126/scitranslmed.aax4846. View

20.

Gaston T, Bebin E, Cutter G, Liu Y, Szaflarski J . Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017; 58(9):1586-1592. DOI: 10.1111/epi.13852. View