glyceryl-2-arachidonate and Epilepsy

The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE).. We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE.. A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 +/- 1.78 pmol/ml; healthy controls = 11.65 +/- 7.53 pmol/ml; n = 9 for both groups, p < 0.01). 2-AG levels, however, were not affected (epileptic patients = 209.5 +/- 146.56; healthy controls = 159.6 +/- 110.2) (n = 6 for both groups, p = 0.48).. Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Disease Models, Animal; Endocannabinoids; Epilepsy; Epilepsy, Temporal Lobe; Female; Glycerides; Hippocampus; Humans; Male; Middle Aged; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Endocannabinoids have paradoxical effects on the mammalian nervous system: Sometimes they block neuronal excitability and other times they augment it. In their Perspective, Mechoulam and Lichtman discuss new work (Marsicano et al.) showing that activation of the cannabinoid receptor CB1 by the endocannabinoid anandamide protects against excitotoxic damage in a mouse model of kainic acid-induced epilepsy.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Brain; Brain Diseases; Cannabidiol; Cannabinoid Receptor Modulators; Cannabinoids; Convulsants; Dronabinol; Endocannabinoids; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Glycerides; Humans; Kainic Acid; Mice; Neurons; Neuroprotective Agents; Polyunsaturated Alkamides; Rats; Receptors, Cannabinoid; Receptors, Drug; Signal Transduction

Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.

Topics: Animals; Arachidonic Acids; Brain; Brain-Derived Neurotrophic Factor; Cannabinoids; Endocannabinoids; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Furans; gamma-Aminobutyric Acid; Gene Expression Regulation; Genes, Immediate-Early; Glutamic Acid; Glycerides; Hippocampus; In Vitro Techniques; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinases; Mutation; Neurons; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Prosencephalon; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Signal Transduction