Journal ArticleDOI
The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy
Reads0
Chats0
TLDR
A role for the endogenous cannabinoid system in modulating neuroexcitation is defined and plasticity of the CB1 receptor occurs with epilepsy, and data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration.Abstract:
Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Delta9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.read more
Citations
More filters
Journal ArticleDOI
The Endocannabinoid System as an Emerging Target of Pharmacotherapy
TL;DR: A comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy is provided.
Journal ArticleDOI
The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin
TL;DR: This review focuses on the manner with which three of these compounds, (−)‐trans‐Δ 9‐tetrahydrocannabinol (Δ9‐THC), (−]‐cannabidiol (CBD) and (−)-trans‐ Δ9‐TetrahYDrocannabivarin (Γ‐THCV), interact with cannabinoid CB1 and CB2 receptors.
Journal ArticleDOI
Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.
Shenglong Zou,Ujendra Kumar +1 more
TL;DR: It is believed that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
Journal ArticleDOI
A tale of two cannabinoids : The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol
Ethan B. Russo,Geoffrey Guy +1 more
TL;DR: The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported, and prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are examined.
Journal ArticleDOI
Endocannabinoid signaling as a synaptic circuit breaker in neurological disease
István Katona,Tamás F. Freund +1 more
TL;DR: Recent advances show that endocannabinoid signaling is a key regulator of synaptic communication throughout the central nervous system and offers new therapeutic opportunities for the selective control of deleterious neuronal activity in several neurological disorders.
References
More filters
Journal ArticleDOI
Isolation and structure of a brain constituent that binds to the cannabinoid receptor
William A. Devane,Lumir Hanus,Aviva Breuer,Roger G. Pertwee,Lesley A. Stevenson,Graeme Griffin,Dan Gibson,Asher Mandelbaum,A. Etinger,Raphael Mechoulam +9 more
TL;DR: In this article, an arachidonylethanthanolamide (anandamide) was identified in a screen for endogenous ligands for the cannabinoid receptor and its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and confirmed by synthesis.
Journal ArticleDOI
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.
Raphael Mechoulam,Shimon Ben-Shabat,Lumir Hanus,Moshe Ligumsky,Norbert E. Kaminski,Anthony R. Schatz,Asher Gopher,Shlomo Almog,Billy R. Martin,David R. Compton,Roger G. Pertwee,Graeme Griffin,Michael Bayewitch,Jacob Barg,Zvi Vogel +14 more
TL;DR: Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature.
Journal ArticleDOI
Cannabinoid receptor localization in brain
TL;DR: The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in the in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience.
Journal ArticleDOI
Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.
Rachel Wilson,Roger A. Nicoll +1 more
TL;DR: The transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons is mediated by retrograde signalling through release of endogenous cannabinoids, indicating that the function of endogenous cannabinoid released by depolarized hippocampal neurons might be to downregulate GABA release.
Journal ArticleDOI
A second endogenous cannabinoid that modulates long-term potentiation
TL;DR: 2-AG activates neuronal cannabinoid receptors as a full agonist, and prevents the induction of long-term potentiation at CA3–CA1 synapses, indicating that 2-AG is a second endogenous cannabinoid ligand in the central nervous system.
Related Papers (5)
CB1 cannabinoid receptors and on-demand defense against excitotoxicity.
Giovanni Marsicano,Sharon Goodenough,Sharon Goodenough,Krisztina Monory,Heike Hermann,Matthias Eder,Astrid Cannich,Shahnaz Christina Azad,Maria Grazia Cascio,Silvia Ortega Gutierrez,Mario van der Stelt,María L. López-Rodríguez,Emilio Casanova,Günther Schütz,Walter Zieglgänsberger,Vincenzo Di Marzo,Christian Behl,Beat Lutz +17 more
The endocannabinoid system controls key epileptogenic circuits in the hippocampus.
Krisztina Monory,Federico Massa,Federico Massa,Michaela Egertová,Matthias Eder,Heike Blaudzun,Ruth E. Westenbroek,Wolfgang Kelsch,Wolfgang Jacob,Rudolf Marsch,Marc Ekker,Jason E. Long,John L.R. Rubenstein,Sandra Goebbels,Klaus-Armin Nave,Matthew J. During,Matthias Klugmann,Barbara Wölfel,Hans-Ulrich Dodt,Walter Zieglgänsberger,Carsten T. Wotjak,Ken Mackie,Maurice R. Elphick,Giovanni Marsicano,Giovanni Marsicano,Beat Lutz +25 more