Δ9-Tetrahydrocannabinol protects hippocampal neurons from excitotoxicity (original) (raw)
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Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity
Molecular Pharmacology, 2005
Nonstandard abbreviations: CB1 cannabinoid receptor (CB1R); protein kinase A (PKA); dibutyryl-cyclic adenosine monophosphate (dbcAMP); R(+)-[2, 3-dihydro-5methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1naphthalenyl)methanone mesylate (R(+)-WIN 55212); N-(piperidin-1-yl)-5-(4chlorophenyl)-1-(2,4-cichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A); 7-nitroindazole (7-NI); N-ω-nitro-L-arginine methyl ester (L-NAME); N[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide (H-89); pertussis toxin (PTX); nitric oxide synthase (NOS); minimal essential medium (MEM); lactate dehydrogenase (LDH); Hepes-buffered control salt solution (HCSS); fluorescein isothiocyanate (FITC)
Modulation of the endocannabinoid system: Neuroprotection or neurotoxicity
Experimental Neurology, 2010
There is now a large volume of data indicating that compounds activating cannabinoid CB1 receptors, either directly or indirectly by preventing the breakdown of endogenous cannabinoids, can protect against neuronal damage produced by a variety of neuronal “insults”. Given that such neurodegenerative stimuli result in increased endocannabinoid levels and that animals with genetic deletions of CB1 receptors are more susceptible to the deleterious effects of such stimuli, a case can be made for an endogenous neuroprotective role of endocannabinoids. However, this is an oversimplification of the current literature, since (a) compounds released together with the endocannabinoids can contribute to the neuroprotective effect; (b) other proteins, such as TASK-1 and PPARα, are involved; (c) the CB1 receptor antagonist/inverse agonist rimonabant has also been reported to have neuroprotective properties in a number of animal models of neurodegenerative disorders. Furthermore, the CB2 receptor located on peripheral immune cells and activated microglia are potential targets for novel therapies. In terms of the clinical usefulness of targeting the endocannabinoid system for the treatment of neurodegenerative disorders, data are emerging, but important factors to be considered are windows of opportunity (for acute situations such as trauma and ischemia) and the functionality of the target receptors (for chronic neurodegenerative disorders such as Alzheimer's disease).
The dual neuroprotective-neurotoxic profile of cannabinoid drugs
British Journal of Pharmacology, 2011
Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/ neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of D 9-tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long-lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre-or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed.
Neuroprotective Properties of Cannabinoids in Cellular and Animal Models: Hypotheses and Facts
2020
Progressive neuronal loss is a typical characteristic of neurodegenerative diseases. In Parkinson’s disease, the loss of dopaminergic neurons in the basal ganglia results in impaired mobility and flawed muscle control. The loss of cholinergic neurons largely in the basal forebrain contributes to memory and attention deficits and the overall cognitive impairment in Alzheimer’s disease. This being said, neuroprotective drugs should be expected to preserve and/or restore the functions affected by neuronal loss, and substantially prevent cell death. The endocannabinoid system, comprising lipid mediators able to bind to and activate cannabinoid receptors, has emerged as a therapeutic target of potential interest in a variety of central nervous system diseases. Palmitoylethanolamide (PEA) is one of the most important endocannabinoids, which has a key role in modulating oxidative stress and inflammatory response with neuroprotective potential in neurological disorders. Neurodegenerative di...
Journal of Neurochemistry, 2002
The ability of cannabinoid CB 1 receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB 1 receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB 1 /CB 2 receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB 1 and SR144528 for CB 2 ) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA-induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB 1 receptor function. In contrast, blockade of CB 1 , but not CB 2 , receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest a critical involvement of CB 1 receptor tonus on neuronal survival following NMDA receptorinduced excitotoxicity in vivo. Abbreviations used: CB 1 receptor, cannabinoid receptor subtype 1; CB 2 receptor, cannabinoid receptor subtype 2; GFAP, glial fibrilary acidic protein; KPBS, potassium phosphate-buffered saline; PBS, phosphate-buffered saline; D 9 -THC, D 9 -tetrahydrocannabinol; TdT, terminal deoxynucleotidyltransferase; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling.
Journal of neurochemistry, 2002
The ability of cannabinoid CB(1) receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB(1) receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB(1) /CB(2) receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB(1) and SR144528 for CB(2) ) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA-induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB(1) receptor function. In contrast, blockade of CB(1), but not CB(2), receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest a critical involvement of CB(1) receptor tonus on neurona...
Experimental Neurology, 2007
Cannabinoids (CBs) are attributed neuroprotective effects in vivo. Here, we determined the neuroprotective potential of CBs during neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures (OHSCs). OHSCs are the best characterized in vitro model to investigate the function of microglial cells in neuronal damage since blood-borne monocytes and T-lymphocytes are absent and microglial cells represent the only immunocompetent cell type. Excitotoxic neuronal damage was induced by NMDA (50 μM) application for 4 h. Neuroprotective properties of 9-carboxy-11-nor-delta-9-tetrahydrocannabinol (THC), N-arachidonoylethanolamide (AEA) or 2-arachidonoylglycerol (2-AG) in different concentrations were determined after co-application with NMDA by counting degenerating neurons identified by propidium iodide labeling (PI +) and microglial cells labeled by isolectin B 4 (IB 4 +). All three CBs used significantly decreased the number of IB 4 + microglial cells in the dentate gyrus but the number of PI + neurons was reduced only after 2-AG treatment. Application of AM630, antagonizing CB2 receptors highly expressed by activated microglial cells, did not counteract neuroprotective effects of 2-AG, but affected THC-mediated reduction of IB 4 + microglial cells. Our results indicate that (1) only 2-AG exerts neuroprotective effects in OHSCs; (2) reduction of IB 4 + microglial cells is not a neuroprotective event per se and involves other CB receptors than the CB2 receptor; (3) the discrepancy in the neuroprotective effects of CBs observed in vivo and in our in vitro model system may underline the functional relevance of invading monocytes and T-lymphocytes that are absent in OHSCs.
Mechanisms of Control of Neuron Survival by the Endocannabinoid System
Current Pharmaceutical Design, 2008
Endocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB 1 cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates in the control of neuron survival. Thus, CB 1 receptor activation has been shown to protect neurons from acute brain injury as well as in neuroinflammatory conditions and neurodegenerative diseases. Nonetheless, some studies have reported that cannabinoids can also exert neurotoxic actions. Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB 1 receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB 1 receptors and growth factor tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB 2 cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation. Altogether, these findings support that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron survival.
A restricted population of CB1 cannabinoid receptors with neuroprotective activity
Proceedings of the National Academy of Sciences, 2014
The CB 1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB 1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB 1 receptor in animal models, the precise pathophysiological relevance of those two CB 1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB 1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB 1 receptors, and (ii) deleting CB 1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB 1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies. neuroprotection | neuromodulation | excitotoxicity E ndocannabinoids are a family of neuron-communication messengers that act by engaging CB 1 cannabinoid receptors, which are also targeted by Δ 9 -tetrahydrocannabinol (THC), the main bioactive component of cannabis. Endocannabinoid signaling serves as a pivotal feedback mechanism to prevent excessive presynaptic activity, thereby tuning the functionality and plasticity of many synapses (1, 2). The CB 1 receptor is the most abundant G protein-coupled receptor in the brain, and is highly expressed in GABAergic terminals of the forebrain (particularly in cholecystokinin-positive and parvalbumin-negative interneurons) (3), where it inhibits GABA release. Functional CB 1 receptors reside as well on terminals of glutamatergic neurons in several brain regions, where they inhibit glutamate release (4). In concert with this well-established neuromodulatory function, the CB 1 receptor protects neurons in many different animal models of acute brain damage and chronic neurodegeneration, which, during recent years, has raised hope about the possible clinical use of cannabinoids as neuroprotective drugs, especially in still unexplored conditions such as Alzheimer's disease, Huntington disease (HD), amyotrophic lateral sclerosis, and stroke (5-7). However, the assessment of the physiological relevance and therapeutic potential of the CB 1 receptor in neurological diseases is hampered, at least in part, by the lack of knowledge of the neuron-population specificity of CB 1 receptor action. Here, by using various genetic models of CB 1 receptor loss of function, together with pharmacological and pharmacogenetic tools, we show that a unique population of CB 1 receptors, namely that located on glutamatergic terminals, plays an indispensable role in the neuroprotective activity of the endocannabinoid system in the mouse brain. This finding opens a new conceptual view on how the CB 1 receptor evokes neuroprotection, and provides preclinical support for improving the development of cannabinoidbased neuroprotective therapies.