Post-ischemic brain damage: the endocannabinoid system in the mechanisms of neuronal death (original) (raw)
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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.
The endocannabinoid system: A new entry in remote cell death mechanisms
Experimental Neurology, 2010
Functional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies. Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems.
Neuropharmacology, 2011
Cannabinoids (CBs) are implicated in a number of physiological and pathological mechanisms in the central nervous system, but their exact role in post-ischemic brain injury is unclear. The toxic and neuroprotective effects of synthetic and endogenous CBs were evaluated in rat organotypic hippocampal slices exposed to 20 min oxygen-glucose deprivation (OGD) and in gerbils subjected to bilateral carotid occlusion for 5 min. When present in the incubation medium, the synthetic CB agonists WIN 55212-2 and CP 55940 (1-30 μM) and the CB1 agonist ACEA exacerbated CA1 injury induced by OGD, whereas the CB1 receptor antagonists AM 251 and LY 320135 were neuroprotective with maximal activity at 1 μM. AM 251 (at 3 mg/kg, i.p.) also attenuated CA1 pyramidal cell death in gerbils in vivo. The endocannabinoid 2-arachidonoylglycerol (2-AG) reduced OGD injury in hippocampal slices at 0.1-1 μM, whereas anandamide (AEA) was neurotoxic at the same concentrations. The effects of WIN 55212-2, AEA and 2-AG in slices were all dependent on the activation of CB1 but not CB2 receptors, except for the toxic effects of AEA that were also dependent on vanilloid TRPV1 receptors. Our results suggest that exogenous administration of CB1 agonists and the production of endocannabinoids "on demand" may produce different, if not opposite, effects on the fate of neurons following cerebral ischemia.
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...
Protective activation of the endocannabinoid system during ischemia in dopamine neurons
Neurobiology of Disease, 2006
Endocannabinoids act as neuroprotective molecules promptly released in response to pathological stimuli. Hence, they may represent one component of protection and/or repair mechanisms mobilized by dopamine (DA) neurons under ischemia. Here, we show that the endocannabinoid 2-arachidonoyl-glycerol (2-AG) plays a key role in protecting DA neurons from ischemia-induced altered spontaneous activity both in vitro and in vivo. Accordingly, neuroprotection can be elicited through moderate cannabinoid receptor type-1 (CB1) activation. Conversely, blockade of endocannabinoid actions through CB1 receptor antagonism worsens the outcome of transient ischemia on DA neuronal activity. These findings indicate that 2-AG mediates neuroprotective actions by delaying damage and/or restoring function of DA cells through activation of presynaptic CB1 receptors. Lastly, they point to CB1 receptors as valuable targets in protection of DA neurons against ischemic injury and emphasize the need for a better understanding of endocannabinoid actions in the fine control of DA transmission.
Proceedings of The National Academy of Sciences, 1996
The amino acid L-glutamate is a neurotrans-mitter that mediates fast neuronal excitation in a majority of synapses in the central nervous system. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stimulation (excitotoxicity) is thought to be primarily responsible for neuronal injury in a wide variety of acute neurological disorders including hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolamide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmitoylethanolamide, but not the cognate N-acylamide anandamide (the ethanolamide of arachidonic acid), protects cultured mouse cerebellar granule cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependent manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also prevented neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of the active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharmacological behaviors have been observed for palmitoylethanolamide (ALI-Amides) in downmodulating mast cell activation. Cerebellar granule cells expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon agonist binding, the downstream consequences of an excitotoxic stimulus; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for CB2-like receptors on granule cells; and (iii) activation of such receptors may serve to downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the nervous and immune systems.
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).
Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Marijuana and related drugs (cannabinoids) have been proposed as treatments for a widening spectrum of medical disorders. R(+)-[2, 3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate (R(+)-WIN 55212-2), a synthetic cannabinoid agonist, decreased hippocampal neuronal loss after transient global cerebral ischemia and reduced infarct volume after permanent focal cerebral ischemia induced by middle cerebral artery occlusion in rats. The less active enantiomer S(-)-WIN 55212-3 was ineffective, and the protective effect of R(+)-WIN 55212-2 was blocked by the specific central cannabinoid (CB1) cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride. R(+)-WIN 55212-2 also protected cultured cerebral cortical neurons from in vitro hypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observed in vivo, this in...
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.