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,...  Read more

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.

View all comments by Nathaniel Milton

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...  Read more

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.

View all comments by Christian Behl

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...  Read more

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.

View all comments by Patrick May

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....  Read more

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.

View all comments by Beat Lutz

This is an excellent paper and it markedly focuses on the importance of both reactive gliosis and the cannabinoid receptor involvement in Alzheimer disease. Targeting reactive gliosis may represent a new, promising approach to inhibit progression of Alzheimer disease (AD). It should be interesting to see in the future the effect of β amyloid on reactive gliosis and relative CB2 expression in specific hippocampal areas. Moreover, a possible cross-talk between specific CA1, CA2, and CA3 neurons with reactive microglia needs further investigation.

View all comments by Giuseppe Esposito

This is probably the best paper on the subject I have seen yet. If CB1 receptors in the brain could be utilized in programmed cell death we could have a brilliant first step in finding a cure for AD. And since antibodies and complement proteins are involved in response to amyloid, CB2 receptors could be manipulated to downregulate cytokines MHC, HLA, and MAC (major histocompatibility molecule, human leuokocyte antigen, membrane attack complex, respectively).

Furthermore, this could also provide a new way of changing expression of protein kinases, phosphatases, ER response to stress. THC could prove very useful in preserving, returning, and even increasing neuronal functions and thus memory and functioning in society. On a final note, glia have been found themselves to be imperative to learning and transmitting messages to neurons. Superb paper!

View all comments by Jacob Mack

Considering data from Ramírez et al. (2005), we can effectively conclude that the endocannabinoid system may be a promising therapeutic target in Alzheimer disease (AD). This report shows the first functional evidence on neuroprotective effects of CB1 and CB2 agonists in in vivo and in vitro models of AD. Further, these authors have found that both CB1 and CB2 agonists are capable of preventing amyloid-β-induced microglial activation and improving behavioral performance in a rat model of AD. Although difficult to connect with results obtained in rats, data from human samples showed a decrease in CB1 functional coupling. The authors also indicate that CB1 protein seems to be decreased in neuronal elements located on the vicinity of BA plaques.

This paper contains some discrepancies with previous data reported by us and others. For instance, while we recently reported CB2 expression in microglial cells in amyloid-β plaques (Benito et al., 2003), Ramírez et al. show only neuronal staining for these receptors. Further, these new data add more controversy to the precise role(s)...  Read more

Considering data from Ramírez et al. (2005), we can effectively conclude that the endocannabinoid system may be a promising therapeutic target in Alzheimer disease (AD). This report shows the first functional evidence on neuroprotective effects of CB1 and CB2 agonists in in vivo and in vitro models of AD. Further, these authors have found that both CB1 and CB2 agonists are capable of preventing amyloid-β-induced microglial activation and improving behavioral performance in a rat model of AD. Although difficult to connect with results obtained in rats, data from human samples showed a decrease in CB1 functional coupling. The authors also indicate that CB1 protein seems to be decreased in neuronal elements located on the vicinity of BA plaques.

This paper contains some discrepancies with previous data reported by us and others. For instance, while we recently reported CB2 expression in microglial cells in amyloid-β plaques (Benito et al., 2003), Ramírez et al. show only neuronal staining for these receptors. Further, these new data add more controversy to the precise role(s) that CB1 and CB2 receptors may play in pathological conditions. Specifically, the pro- or antiinflammatory effect of CB2 activation is a hot issue. Cece Hillard´s (Carrier et al., 2004) and Nephi Stella´s (Walter et al., 2003) groups have reported increased in vitro proliferation and migration of microglia, respectively, while Klegeris et al. (2003) have postulated CB2 receptors as mediators of antiinflammatory events.

One important question that should be addressed is the role of endogenous cannabinoids in AD. As we suggested in a previous paper (Pazos et al., 2004), these arachidonic acid-related compounds may have a double-sided role as, together with their recognized antiinflammatory properties, they may also be easily metabolized to arachidonic acid derivatives, well-known for their proinflammatory actions.

Researchers working on cannabinoids are used to the amplification of experimental results by mass media. In fact, sometimes we all get benefits from it. Other times, however, misleading information may result. I agree this may be the case for a sentence like, “Marijuana may block Alzheimer´s.”

References:
Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005 Feb 23;25(8):1904-13. Abstract

Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ, Romero J. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. J Neurosci. 2003 Dec 3;23(35):11136-41. Abstract

Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ. Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol. 2004 Apr;65(4):999-1007. Abstract

Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci. 2003 Feb 15;23(4):1398-405. Abstract

Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol. 2003 Jun;139(4):775-86. Abstract

Pazos MR, Nunez E, Benito C, Tolon RM, Romero J. Role of the endocannabinoid system in Alzheimer's disease: new perspectives. Life Sci. 2004 Sep 3;75(16):1907-15. Review. Abstract

View all comments by Julian Romero

Comment by Pat McGeer and Andis Klegeris
Ramirez et al., in their paper on prevention of Alzheimer disease pathology by cannabinoids, concluded that “cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.” This conclusion is open to question. It is based on a series of experiments demonstrating the antiinflammatory effects of stimulating CB2 receptors. However, the authors did not investigate the effects of stimulating selectively CB1 receptors.

Cannabinoids such as Δ-9 THC stimulate both CB1 and CB2 receptors. CB1 agonists are toxic to several types of neuronal cells in vitro (Blevins and Regan, 1976; Chan et al., 1998; Klegeris et al., 2003; Lew, 1996). In vivo data show that Δ-9 THC can cause neuronal death after prolonged exposure periods (Scallet, 1991). Heavy use of cannabis is also known to have deleterious effects on cognition and memory (Pope and Yurgelun-Todd, 1996; Solowij et al., 2002), despite some reports of the neuroprotective effects of cannabinoids (for review see Guzman et al., 2001).

Ramirez et al....  Read more

Comment by Pat McGeer and Andis Klegeris
Ramirez et al., in their paper on prevention of Alzheimer disease pathology by cannabinoids, concluded that “cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.” This conclusion is open to question. It is based on a series of experiments demonstrating the antiinflammatory effects of stimulating CB2 receptors. However, the authors did not investigate the effects of stimulating selectively CB1 receptors.

Cannabinoids such as Δ-9 THC stimulate both CB1 and CB2 receptors. CB1 agonists are toxic to several types of neuronal cells in vitro (Blevins and Regan, 1976; Chan et al., 1998; Klegeris et al., 2003; Lew, 1996). In vivo data show that Δ-9 THC can cause neuronal death after prolonged exposure periods (Scallet, 1991). Heavy use of cannabis is also known to have deleterious effects on cognition and memory (Pope and Yurgelun-Todd, 1996; Solowij et al., 2002), despite some reports of the neuroprotective effects of cannabinoids (for review see Guzman et al., 2001).

Ramirez et al. reported a reduction of CB1-expressing neurons in AD, which would be consistent with the previous data on the deleterious effects of CB1 stimulation. Destruction of neurons in AD could be enhanced by endogenous CB1 agonists such as anandamide.

Ligands selective for CB2, such as JWH 015 and indomethacin morpholinylamide are a safer class to pursue in search of antiinflammatory agents for the treatment of AD. CB2 is strongly expressed by immune system cells (Cabral and Dove Pettit, 1998; Klein et al., 1998), including human and rodent microglia (Klegeris et al., 2003; Walter et al., 2003), but it is not expressed by human neuroblastoma SH SY5Y cells (Klegeris et al., 2003). Agonists of CB2, but not CB1, prevent activated microglia from secreting neurotoxic materials into culture supernatant (Klegeris et al., 2003), reinforcing previous reports of their antiinflammatory activity.

In summary, cannabis ingredients stimulate both CB1 and CB2, so they have the potential to damage neurons directly, even though they may also protect them indirectly. The best approach is to concentrate on selective CB2 agonists.

References:
Blevins RD, Regan JD. 1976. Delta-9-Tetrahydrocannabinol: effect on macromolecular synthesis in human and other mammalian cells. Arch Toxicol 35:127-135. Abstract

Cabral GA, Dove Pettit DA. 1998. Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease. J Neuroimmunol 83:116-123. Abstract

Chan GC, Hinds TR, Impey S, Storm DR. 1998. Hippocampal neurotoxicity of delta-9-tetrahydrocannabinol. J Neurosci 18:5322-5332. Abstract

Guzman M, Sanchez C, Galve-Roperh I. 2001. Control of the cell survival/death decision by cannabinoids. J Mol Med 78:613-625. Abstract

Klegeris A, Bissonnette CJ, McGeer PL. 2003. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid type CB2 receptor. Brit J Pharmacol 139:775-786. Abstract

Klein TW, Newton C, Friedman H. 1998. Cannabinoid receptors and immunity. Immunol Today 19:373-381. Abstract

Lew GM. 1996. Tau protein after delta-9-tetrahydrocannabinol in a human neuroblastoma cell line. Gen Pharmac 27:1141-1143. Abstract

Pope HG, Yurgelun-Todd D. 1996. The residual cognitive effects of heavy marijuana use in college students. JAMA 275:521-527. Abstract

Scallet AC. 1991. Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals. Pharmacol Biochem Behav 40:671-676. Abstract

Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B, Vendetti J, The, Marijuana, Treatment, Project, Research, Group. 2002. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA 287:1123-1131. Abstract

Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N. 2003. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398-1405. Abstract

View all comments by P.L. McGeer

Pat McGeer makes an interesting point, but further review of the research shows that agonists of CB1 receptors can in fact be neuroprotective. It is quite possible to manipulate CB1 receptors to induce apoptosis in affected neurons (i.e. those with amyloid deposits). In vivo experiments have suggested possible therapeutic treatments utilizing CB1 receptors.

Some experiments point to damge caused by overstimulation of CB2 receptors, as well, but more research is needed to properly utilize agonist/antagonist signals to manipulate the immune response in AD patients. Check out some of the research coming out of Canada as early as 1998. Fatty acid cannabinoid-like brain chemicals show much promise in helping treat AD, slowing progression, and possibly devloping new preventive measures.

View all comments by Jacob Mack

This is a very well-designed study that adds up to the accumulating evidence on cannabinoid-mediated neuroprotection. It shows many aspects of their beneficial effects, in experimental models (both in-vitro and in-vivo), and highlights the effect of cannabinoids on activated microglia, namely, on inflammatory processes. The experimental findings are supported by findings from clinical material of AD patients, and the authors propose that attenuation of long-lasting inflammatory reaction by cannabinoids may prevent neurodegenerative processes.

Studies from our own (Panikashvili et al. 2001; 2005) and many other laboratories well agree with this concept. Yet, in contrast to the large body of evidence suggesting a neuroprotective role of cannabinoids, another paper should be cited that, like Pat McGeer’s group, reports the toxic effect of anandamide {“The dark side of endocannabinoids” : A neurotoxic role for anandamide, (Cernak et al., 2004)). I am not sure yet how to reconcile between these conflicting data.

Our group is interested in the pathophysiology of traumatic...  Read more

This is a very well-designed study that adds up to the accumulating evidence on cannabinoid-mediated neuroprotection. It shows many aspects of their beneficial effects, in experimental models (both in-vitro and in-vivo), and highlights the effect of cannabinoids on activated microglia, namely, on inflammatory processes. The experimental findings are supported by findings from clinical material of AD patients, and the authors propose that attenuation of long-lasting inflammatory reaction by cannabinoids may prevent neurodegenerative processes.

Studies from our own (Panikashvili et al. 2001; 2005) and many other laboratories well agree with this concept. Yet, in contrast to the large body of evidence suggesting a neuroprotective role of cannabinoids, another paper should be cited that, like Pat McGeer’s group, reports the toxic effect of anandamide {“The dark side of endocannabinoids” : A neurotoxic role for anandamide, (Cernak et al., 2004)). I am not sure yet how to reconcile between these conflicting data.

Our group is interested in the pathophysiology of traumatic brain injury (TBI) and we study the role of cannabinoids, both endogenous and exogenous, in closed head injury, a mouse model of TBI. We have reported that the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) increased 10-fold within 4 hours after injury in mice, and that when injected after injury, the synthetic 2-AG improved outcome (Panikashvili et al., 2001). We extended our studies and showed that this effect is indeed CB1 receptor mediated by using CB1 knockout (KO) mice. The recovery of the KO mice was slower than that of the wild-types, and they did not respond to treatment with exogenous 2-AG (Panikashvili et al. 2005 ). The mechanism proposed in our recent study (Panikashvili et al. 2005) is that 2-AG inhibits the activation (nuclear translocation) of the transcription factor NF-kappaB, which is a “master” regulator of the inflammatory response. NF-kappaB has been shown to be involved in brain damage and to promote neuronal cell death in in-vitro and in in-vivo models of ischemic and neurodegenerative neurological diseases. Thus, the inhibition of TNFαrelease reported by Ramirez et al. is well explained by the inhibition of NF-kappaB, as shown for 2-AG (our own findings) and HU-211 (dexanabinol) by Juttler et al. (2004). However, the latter authors show that inhibition of NF-kappaB by cannabinoids is not mediated via the CB1 or CB2 receptors. In addition, we found (Panikashvili et al., abstract presented at 2004 Neuroscience meeting, and full paper submitted for publication) that 2-AG inhibited the acute (1-4 h) post traumatic expression of the main proinflammatory cytokines: TNF-α, IL-1β and IL-6.

In conclusion, the study by Ramirez et al is an important contribution to the field of cannabinoids as neuroprotective agents, and, supported by others, strongly favors its anti-inflammatory effects as one of its mechanism of action.

References:
Cernak I, Vink R, Natale J, Stoica B, Lea PM 4th, Movsesyan V, Ahmed F, Knoblach SM, Fricke ST, Faden AI The "dark side" of endocannabinoids: a neurotoxic role for anandamide. J Cereb Blood Flow & Metabol 24: 564, 2004

Juttler E, Potrovita I, Tarabin V, Prinz S, Dong-Si T, Fink G, Schwaninger M. The cannabinoid dexanabinol is an inhibitor of the nuclear factor-kappa B (NF-kappa B). Neuropharmacology 47:580-592, 2004

Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 413:527-531. 2001

Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E. CB(1) cannabinoid receptors are involved in neuroprotection via NF-kappaB inhibition. J Cereb Blood Flow Metab. 2005 Feb 23; [Epub ahead of print]

View all comments by Esther Shohami