The same brain machinery that responds to the active substance in marijuana provides a central "on-demand" protection against seizures, researchers have found. They said their discoveries suggest that the "endocannabinoid" system might constitute a prime target for drugs against seizures of epilepsy and other neurodegenerative diseases.
The findings were published by Beat Lutz and Giovanni Marsicano, of Max Planck Institute of Psychiatry and Johannes Gutenberg University in Mainz, and colleagues in the August 17, 2006, issue of the journal Neuron, published by Cell Press.
The endocannabinoid system--which includes the receptors, the natural cannabinoid compounds that trigger them, as well as the machinery for regulating the process--was already known to modulate the excitation of neuronal transmission, noted the researchers. However, it had not been established that such modulation might affect neurons in the hippocampus responsible for the "excitotoxicity" that underlies the uncontrolled activity of seizures.
Thus, Lutz, Marsicano, and his colleagues used genetic techniques to pinpoint the role of the endocannabinoid system on these neurons and on seizure activity. They used mice as their animal model and induced seizures in these mice with the chemical kainic acid (KA).
In particular, they wanted to explore the role played by the endocannabinoid system in hippocampal neurons that are responsive to the neurotransmitter glutamine. These neurons are known to play a central role in seizure activity. The endocannabinoid regulatory system is also active in another type of neuron triggered by the neurotransmitter gamma-aminobutyric acid (GABA).
Thus, the researchers conducted experiments in which they genetically knocked out the endocannabinoid receptor CB1 and analyzed the effects on seizure sensitivity. They found that, indeed, when they knocked out CB1 in glutamatergic, but not GABAergic neurons, the chemically induced seizures increased in the mice. In fact, their experiments all but ruled out the role of GABAergic neurons in the seizure-protection function, they concluded.
"Altogether, these results confirm that physiological endocannabinoid-dependent control of GABAergic transmission depends on intact CB1 signaling in GABAergic interneurons and suggest that the endocannabinoid system does not influence GABAergic transmission during the development of KA-induced seizures," they concluded. "Therefore, direct modulation of glutamatergic transmission by CB1 receptors expressed on cortical glutamatergic neurons appears to be the major mechanism of endocannabinoid-mediated protection against KA-induced seizures."
Furthermore, the researchers' experiments established that endocannabinoid receptors were also present in the same glutamatergic neurons in areas of the hippocampus known to be central to seizure generation. The researchers wrote that this finding "represents a novel step in understanding the progression of acute excitotoxic seizures and the development of epileptic states."
And significantly, when the researchers used a targeted virus to knock out the CB1 gene for the endocannabinoid receptor specifically in the glutamatergic neurons of the hippocampus, the mice also showed strong worsening of chemically induced seizures in comparison to mice still expressing CB1.
"Altogether, these observations support a hypothetical scenario in which acute KA-induced excitotoxic seizures would activate the endocannabinoid system in respect to its ability to inhibit only 'harmful' glutamatergic transmission, but not 'protective' GABAergic release," concluded Lutz, Marsicano, and colleagues.
"In conclusion, our study reveals a mechanism through which the endocannabinoid system is able to provide on-demand protection against acute behavioral seizures. CB1 expression on hippocampal glutamatergic circuits accounts for this protection and might represent a suitable target for the treatment of neurological disorders associated with excessive neuronal excitation," they wrote.
The researchers include Krisztina Monory, Federico Massa, and Beat Lutz of Johannes Gutenberg University in Mainz, Germany and Max Planck Institute of Psychiatry in Munich, Germany; Michaela Egertová and Maurice R. Elphick of Queen Mary, University of London in London, United Kingdom; Matthias Eder, Heike Blaudzun, Wolfgang Kelsch, Wolfgang Jacob, Rudolf Marsch, Barbara Wölfel, Hans-Ulrich Dodt, Walter Zieglgänsberger, and Carsten T. Wotjak of Max Planck Institute of Psychiatry in Munich, Germany; Ruth Westenbroek and Ken Mackie of University of Washington in Seattle, WA; Marc Ekker of University of Ottawa in Ottawa, Ontario, Canada; Jason Long and John L. Rubenstein of University of California, San Francisco in San Francisco, CA; Sandra Goebbels and Klaus-Armin Nave of Max Planck Institute of Experimental Medicine in Göttingen, Germany; Matthew During of University of Auckland School of Medicine in Auckland, New Zealand; Matthias Klugmann of Auckland School of Medicine in Auckland, New Zealand and University of Heidelberg in Heidelberg, Germany; Giovanni Marsicano of Johannes Gutenberg University in Mainz, Germany, Max Planck Institute of Psychiatry in Munich, Germany, and AVENIR INSERM, Institute François Magendie in Bordeaux, France.
Grant support was as follows: Marie Curie Fellowship QLG1-CT-2002-51742 (to K. Monory); CIHR MOP14460 (to M.E.); Nina Ireland, MH49428 and MH065670 (to J.R.); DA00286, DA11322, and DA15916 (to K. Mackie); BBSRC S19916 (to M.R.E.); Deutsche Forschungsgemeinschaft (DFG) LU755/1-3 and a scholarship from the Hertie Foundation (to B.L.).
Monory et al.: "The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus." Publishing in Neuron 51, 455--466, August 17, 2006 DOI 10.1016/j.neuron.2006.07.006 www.neuron.org
Related Preview by Alger et al.: "Preview: Not Too Excited? Thank Your Endocannabinoids."
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