. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003 Oct 3;302(5642):84-8. PubMed.

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  1. This is an excellent paper. The selective expression studies clearly demonstrate that the location of CB1 cannabinoid receptors plays a distinct role in neuroprotection by endogenous cannabinoids. The role of endogenous cannabinoids in the protection against kainic acid-induced neurotoxicity is also demonstrated. The ability of anandamide uptake inhibitors to protect mice against kainic acid-induced seizures, and the requirement for CB1 receptor expression in glutaminergic but not GABAergic neurons, suggests that the endogenous cannabinoid system protects via direct actions on the glutaminergic system.

    The model system employed suggests that hippocampal neurons' expression of CB1 receptors is involved in the response. In view of the marked hippocampal damage seen in Alzheimer's disease, this suggests that manipulation of the endogenous cannabinoid system may have potential as a neuroprotective strategy. The ability of endocannabinoids, including anandamide, to protect against amyloid-β in vitro (Milton, 2002) had suggested a therapeutic potential of cannabinoids for Alzheimer's neurodegeneration. This paper by Marsicano et al. provides in-vivo evidence.

    This study suggests that manipulation of the endogenous cannabinoid system, rather than direct administration of cannabinoids, has potential as a treatment strategy. Neurotoxic actions of cannabinoids at high doses make this particularly relevant. The availability of selective anandamide uptake inhibitors, which enhance activity by preventing anandamide breakdown, and the potential of directly inhibiting the enzymes involved in endogenous cannabinoid breakdown, may be a useful route to future Alzheimer's therapy.

    I recommend this work, and look forward to reading a follow-up study on the role of endogenous cannabinoids in protecting against amyloid-β toxicity in vivo. Senior authors Christian Behl and Beat Lutz have previously published papers related to amyloid-β, and hopefully, they are already performing such a study in their excellent model system.

  2. Reply to Nathanial Milton:

    Indeed, several different groups have shown that compounds that can activate the cannabinoid receptor prevent the toxicity of amyloid-β peptide and of other oxidative insults in cell cultures. We ourselves reported about two years ago that some of these compounds may even act as active free radical scavengers independent of any receptor activation (Marsicano et al. 2002). Nevertheless, as Nathanial Milton is correctly stating in his comment, we have now found that the body's own, self-made cannabinoids (endocannabinoids) safeguard the brain on demand. Since my group has a longstanding interest in Alzheimer's disease and novel neuroprotective approaches, we are currently selecting an appropriate Alzheimer's mouse model to study possible protection by endocannabinoids against Alzheimer's-associated neurodegeneration. But there is a big difference between the Alzheimer's and the kainic acid animal model, since the latter is an acute neurotoxic/oxidative insult rather than a slowly increasing challenge as seen in AD models. Despite that, we are intensively working on a possible role of endocannabinoids in the prevention of AD pathology. Our hope is, indeed, that the controlled activation of cannabinoid receptors will be a novel preventive approach, but this needs to be investigated now. In addition, we are looking more closely into another model of acute neurodegeneration, i.e., ischemia/reperfusion, as a relevant model for human stroke. All these studies will be done in close collaboration with the group of Beat Lutz in Munich.

  3. This is an interesting paper examining the potential role of the endocannabinoid system in affording protection against excitotoxic seizures elicited by kainic acid. Clearly, mice lacking CB-1 receptors exhibit more severe behavioral seizures in response to a kainate challenge. Importantly, pharmacological antagonism of the CB-1 receptor in wild-type mice recapitulated the increased behavioral sensitivity observed in the genetic knockout mice. Conversely, pharmacological inhibition of the endocannabinoid re-uptake system significantly, albeit modestly, reduced seizures in response to kainate. Of note, endogenous anandamide levels in the hippocampus of wild type C57Bl/6N mice increased over threefold within 20 minutes of a 30 mg/kg kainate challenge.

    Perhaps the only shortcoming of this paper is that, while a defense mechanism against excitotoxicity offered by the endocannabinoid system is a major focus of the discussion, very little histologic data documenting frank neuronal degeneration in the hippocampus is provided. As reported in a supplemental figure, TUNEL staining and GFAP immunoreactivity in the hippocampus four days after 20 mg/kg kainate were only modestly increased in mice lacking CB-1 receptors. No Nissl stain is provided, but it appears that CA-3 pyramidal neurons are significantly decreased irrespective of CB-1 receptor expression.

    Interestingly, these studies all were conducted in mice that were predominantly on a C57Bl/6N background. In a paper published several years ago, Schauwecker and Steward documented marked strain-dependent differential sensitivity to kainate-induced hippocampal neuronal degeneration (Schauwecker and Steward, 1997). Of several strains studied by them, the C57Bl/6 was one that showed the most resistance to frank neuronal degeneration, despite having behavioral seizures comparable to FVB/N mice that showed robust pyramidal cell loss. It would be interesting to compare the endocannabinoid response to kainate in these two strains of inbred mice. Would FVB/N mice have a blunted response relative to C57Bl/6 mice? From there it’s a short leap to positing polymorphisms and/or age-related changes in the endocannabinoid system leading to differential vulnerability to excitotoxic challenges.

    The therapeutic implications are intriguing. The endogenous anandamide levels increase within 20 minutes of the kainate challenge, but are back to baseline values within an hour, despite ongoing behavioral seizures. These data lead the authors to hypothesize that acute agonist stimulation of the CB-1 receptor offers a sort of on-demand defense against excitotoxic challenges. Whether similar neuroprotective pathways would be elicited and/or maintained under conditions of persistent agonism at the CB-1 receptor is unclear, but warrants testing.

  4. Due to the genetic background used in our study, it is not surprising that the long-term degenerative effects after kainate treatment were only modest. Nevertheless, these effects were significant. Certainly, we would have preferred to work in a more suitable genetic background, since C57BL/6N is known to be very resistant to damage. However, for reasons of time and space in the animal house, we were not able to backcross into, e.g., 129 or other inbred strains.

    The notion that there might be strain differences regarding the endocannabinoid system is actually very interesting. However, no systematic investigations have been performed to the present.

    We think that the concept of on-demand activation of the endocannabinoid system in certain neuronal subpopulations is important for the ability to protect. Persistent agonism at the CB1 receptor was shown to worsen seizures upon kainate treatment, as shown recently by Clement et al.. However, in other models of excitotoxicity, this strategy is successful. It will be interesting to address this issue in more detail in further studies.

    In conclusion, the best strategy may be to modulate the endogenous cannabinoid system by pharmacological treatments aiming to prolong the action of the endocannabinoids. It is noteworthy that such drugs are much less psychoactive than THC and other CB1 antagonists.

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