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Cannabinoids and Epilepsy
Investigational cannabinoids in seizure disorders, what have we learned thus far? Ružić Zečević D(1), Folić M(1), Tantoush Z(1), Radovanović M(1), Babić G(1), Janković SM(1). Author information: (1)a University of Kragujevac , Faculty of Medical Sciences. INTRODUCTION: The anticonvulsant activity of cannabinoids attracted much attention in the last decade. Cannabinoids that are currently investigated with the intention of making them drugs for the treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin and Δ9-tetrahydrocannabinolic acid. Areas covered. In this review, the authors look at the results of pre-clinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR and SCINDEX databases. Expert opinion. Pre-clinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While the results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy resistant seizures associated with Dravet syndrome and in patients with Lennox-Gastaut syndrome who have drop seizures. However, the full therapeutic potential of cannabinoids in treatment-resistant epilepsy needs to be investigated in the near future. 2. Endocannabinoid CB1 receptors are involved in antiepileptogenic effect of low frequency electrical stimulation during perforant path kindling in rats. Mardani P(1), Oryan S(2), Sarihi A(3), Alaei E(3), Komaki A(3), Mirnajafi-Zadeh J(4). Author information: (1)Department of Animal Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran; Department of Biology, Faculty of Sciences, Payame Noor University, Iran. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. (2)Department of Animal Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran. (3)Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. (4)Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. INTRODUCTION: Administration of low-frequency electrical stimulation (LFS) at the kindling site has an antiepileptogenic effect. In the present study, we investigated the role of cannabinoid receptors type 1 (CB1) in mediating the inhibitory effects of LFS on the development of perforant path kindled seizures. METHODS: For seizure generation, rats were kindled by electrical stimulation of perforant path in semi-rapid kindling manner (12 stimulations per day at 10 min intervals at afterdischarge threshold intensity).To determine the effect of LFS (0.1 ms pulse duration at 1 Hz, 800 pulses) on seizure generation, LFS was applied to the perforant path 5 min after the last kindling stimulation daily. AM281, a CB1 receptor antagonist, was microinjected into the lateral ventricle immediately after the last kindling stimulation (before LFS application) at the doses of 0.5 and 2 μg/μl during kindling procedure. The expression of cannabinoid receptors in the dentate gyrus was also investigated using immunohistochemistry. RESULTS: Application of LFS had inhibitory effect on development of kindled seizures (kindling rate). Microinjection of AM281 (0.5 μg/μl) immediately after the last kindling stimulation (before LFS application) reduced the inhibitory effect of LFS on the kindling rate and suppressed the effects of LFS on potentiation (increasing the magnitude) of both population spike amplitude and population excitatory postsynaptic potential slope during kindling acquisition. AM281 pretreatment also prevented the effects of LFS on kindling-induced increase in early and late paired pulse depression. The higher dose of AM281 (2 μg/μl) failed to exert the effects observed with its lower dose (0.5 μg/μl). In addition, there was a decreased CB1 receptors immunostaining in kindled animals compared to control. However, application of LFS following kindling stimulations led to overexpression of CB1 receptors in the dentate gyrus. CONCLUSION: Obtained results showed that activation of overexpressed cannabinoid CB1 receptors by endogenous cannabinoids may have a role in mediating the inhibitory effect of LFS on perforant path kindled seizures. Copyright © 2018. Published by Elsevier B.V. 3. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. Devinsky O(1), Patel AD(1), Cross JH(1), Villanueva V(1), Wirrell EC(1), Privitera M(1), Greenwood SM(1), Roberts C(1), Checketts D(1), VanLandingham KE(1), Zuberi SM(1); GWPCARE3 Study Group. Collaborators: Nabbout R, Bhathal H, Gil-Nagel A, Rodruguez-Uranga J, Sanchez-Carpintero R, Chin R, Bailey R, Barron T, Clarke D, Crepeau A, Davis R, Goyal M, Halford J, Kang H, Madan-Cohen J, Mitchell W, Nahouraii R, Park Y, Perry S, Wechsler R, Weinstock A, Wong M, Dlugos D, French J, Kessler S, Shellhaas R, Sullivan J, Thio LL. Author information: (1)From New York University Langone Comprehensive Epilepsy Center, New York (O.D.); Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus (A.D.P.), and the University of Cincinnati Medical Center, Department of Neurology, Cincinnati (M.P.) - all in Ohio; UCL Great Ormond Street Institute of Child Health, London (J.H.C.), GW Research Ltd., Cambridge (S.M.G., C.R., D.C.), and the Royal Hospital for Children and School of Medicine, University of Glasgow, Glasgow (S.M.Z.) - all in the United Kingdom; Refractory Epilepsy Unit, Neurology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain (V.V.); the Divisions of Child and Adolescent Neurology and Epilepsy, Department of Neurology, Mayo Clinic, Rochester, MN (E.C.W.); and Greenwich Biosciences, Carlsbad, CA (K.E.V.). BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .). 4. Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice. Carvalho RK(1), Santos ML(1), Souza MR(1), Rocha TL(2), Guimarães FS(3), Anselmo-Franci JA(4), Mazaro-Costa R(1). Author information: (1)Department of Pharmacology, Laboratory of Physiology and Pharmacology of Reproduction, Universidade Federal de Goiás, Goiânia, GO, Brazil. (2)Institute of Tropical Pathology and Public Health, Universidade Federal de Goiás, Goiânia, GO, Brazil. (3)Department of Pharmacology, Ribeirão Preto Medical School, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. (4)Department of Morphology, Stomatology and Physiology, Dental School of Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Children and adults with frequent and severe episodes of epilepsy that do not respond to standard treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reproduction has not been fully examined. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21-day-old male Swiss mice at doses of 15 and 30 mg kg-1 daily (CBD 15 and 30 groups, respectively), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: weight of reproductive organs, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiological normal range (240-1100 ng dl-1 ). CBD treatment induced a significant increase in the frequency of stages I-IV and V-VI of spermatogenesis, and a decrease in the frequency of stages VII-VIII and XII. A significant decrease in the number of Sertoli cells was observed only in the CBD 30 group. In both CBD groups the number of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the medial region of flagellum. These results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity. Copyright © 2018 John Wiley & Sons, Ltd.