Cannabinoids and neuronal damage: Differential effects of THC, AEA and 2-AG on activated microglial cells and degenerating neurons in excitotoxically lesioned rat organotypic hippocampal slice cultures

Kreutz, Susanne; Koch, Marco; Ghadban, Chalid; Korf, Horst‐Werner; Dehghani, Faramarz

doi:10.1016/j.expneurol.2006.08.010

Cited by 44 publications

(45 citation statements)

References 63 publications

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“…As we have shown previously, 2-AG reduced the amount of activated microglial cells and protected dentate gyrus (DG) granule cells from damage in excitotoxically (NMDA-) lesioned organotypic hippocampal slice cultures (OHSCs) (Kreutz et al, 2007). These effects of 2-AG were not blocked by the specific CB2 receptor antagonist AM630 raising the hypothesis that the neuroprotective effects of 2-AG in lesioned OHSC may be mediated by abn-CBD-sensitive receptors present on microglial cells.…”

Section: Introductionmentioning

confidence: 78%

“…Notably, we have shown previously that the 2-AG mediated reduction of microglial cells was not inhibited by the CB2 receptor antagonist AM630 (Kreutz et al, 2007) and studies on microglial single cell cultures revealed that 2-AG triggers the migration of microglial cells via activation of abn-CBD-sensitive receptors (Stella, 2004;Pocock and Kettenmann, 2007).…”

Section: Abn-cbd-sensitive Receptor Mediated Neuroprotection Depends mentioning

confidence: 95%

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2‐Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal‐cannabidiol‐sensitive receptors on microglial cells

Kreutz

Koch

Böttger

et al. 2008

Glia

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Endocannabinoids like 2-arachidonoylglycerol (2-AG) exert neuroprotective effects after brain injuries. According to current concepts, these neuroprotective effects are due to interactions between 2-AG and cannabinoid (CB)1 receptors on neurons. Moreover, 2-AG modulates migration and proliferation of microglial cells which are rapidly activated after brain lesion. This effect is mediated via CB2- and abnormal-cannabidiol (abn-CBD)-sensitive receptors. In the present study, we investigated whether the abn-CBD-sensitive receptor on microglial cells contributes to 2-AG-mediated neuroprotection in organotypic hippocampal slice cultures (OHSCs) after excitotoxic lesion induced by NMDA (50 microM) application for 4 h. This lesion caused neuronal damage and accumulation of microglial cells within the granule cell layer. To analyze the role of abn-CBD-sensitive receptors for neuroprotection and microglial cell accumulation, two agonists of the abn-CBD-sensitive receptor, abn-CBD or 2-AG, two antagonists, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen1-yl]-benzene (O-1918) or cannabidiol (CBD), and the CB1 receptor antagonist AM251, were applied to NMDA-lesioned OHSC. Propidium iodide (PI) labeling was used as a marker of degenerating neurons and isolectin B(4) (IB(4)) as a marker of microglial cells. Application of both, abn-CBD or 2-AG to lesioned OHSC significantly decreased the number of IB(4)(+) microglial cells and PI(+) neurons in the dentate gyrus. In contrast to AM251, application of O-1918 or CBD antagonized these effects. When microglial cells were depleted by preincubation of OHSC with the bisphosphonate clodronate (100 microg/mL) for 5 days before excitotoxic lesion, 2-AG and abn-CBD lost their neuroprotective effects. We therefore propose that the endocannabinoid 2-AG exerts its neuroprotective effects via activation of abn-CBD-sensitive receptors on microglial cells.

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Section: Introductionmentioning

confidence: 78%

Section: Abn-cbd-sensitive Receptor Mediated Neuroprotection Depends mentioning

confidence: 95%

2‐Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal‐cannabidiol‐sensitive receptors on microglial cells

Kreutz

Koch

Böttger

et al. 2008

Glia

Self Cite

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“…25 Endogenous cannabinoids exert neuroprotective effects in animal models of various forms of acute neuronal injury such as cerebral ischemia, traumatic brain injury, and neurodegenerative diseases. 5,6,26 In the present study, pretreatment with 2-AG and AEA afforded neuroprotection manifested as the reduction of infarct sizes and improvement of neurological outcomes 24 hours after reperfusion followed by 120 minutes of focal ischemia. Thus, our finding suggests that pretreatment with EA increases the production of the endocannabinoid 2-AG and AEA, which elicit protective effects against transient cerebral ischemia.…”

Section: Discussionmentioning

confidence: 95%

Pretreatment With Electroacupuncture Induces Rapid Tolerance to Focal Cerebral Ischemia Through Regulation of Endocannabinoid System

Wang

Chen

et al. 2009

Stroke

170

118

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Background and Purpose-Our previous study demonstrated that pretreatment with electroacupuncture (EA) induces rapid tolerance to focal cerebral ischemia. The present study was aimed to investigate the involvement of the endocannabinoid system in the early neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia. Methods-Two hours after the end of EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion for 120 minutes in male Sprague-Dawley rats or male C57BL/6 mice. The neurobehavioral scores, infarction volumes, and neuronal apoptosis were evaluated at 24 hours or 7 days after reperfusion in the presence or absence of AM251 (a selective cannabinoid receptor type 1 [CB1] receptor antagonist) or CB1 short interfering RNA. The expression of CB1 receptor and the content of endocannabinoids in the brains were also investigated. Results-EA pretreatment reduced infarct size, improved neurological outcome, and inhibited neuronal apoptosis at 24 hours or 7 days after reperfusion. The beneficial effects were abolished by AM251. CB1 knockdown by CB1 short interfering RNA attenuated EA pretreatment-induced neuroprotection. EA pretreatment upregulated the neuronal expression of CB1 receptor in the rat brains and elevated the brain tissue content of the endocannabinoid 2-arachidonylglycerol and N-arach-idonoylethanolamine-anandamide. Pretreatment with 2-arachidonylglycerol and N-arach-idonoylethanolamine-anandamide also reduced infarct size and improved neurological outcome. Conclusion-We conclude that pretreatment with EA increases the production of endocannabinoid 2-arachidonylglycerol and N-arach-idonoylethanolamine-anandamide, which elicits protective effects against transient cerebral ischemia through CB1 receptors. These results suggest a novel mechanism of EA pretreatment-induced rapid tolerance to focal cerebral ischemia.

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“…However, previous studies revealed decreased AEA levels 36, whereas others observed normal 37 or higher 38 AEA levels in demyelinated brains. In addition, the gene involved in 2‐AG synthesis (Dagla) was declined following CPZ diet and 0.5 mg/kg of WIN although others have found conflicting results 39, 40, 41, 42. This discrepancy might be attributed to the animal model (rats vs. mice), the methods, the sampling time applied, or the target brain structure analyzed.…”

Section: Discussionmentioning

confidence: 99%

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

et al. 2016

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SummaryAim and methodsDifferent types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells. With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.ResultsThe synthetic cannabinoid agonist WIN55212.2 at 1 μM increased the myelin basic protein mRNA and protein expression in vitro. During cuprizone‐induced acute demyelination, the administration of 0.5 mg/kg WIN55212.2 confers more myelinated axons, increased the expression of retinoid X receptor alpha, and declined nogo receptor expression. Controversially, 1 mg/kg of the drug increased the number of demyelinated axons and reduced the expression of nerve growth factor inducible, calreticulin and myelin‐related genes coupling specifically with a decrease in 2′,3′‐cyclic nucleotide 3′ phosphodiesterase expression.ConclusionThe cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro. Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone‐induced demyelination, while 1 mg/kg aggravates the demyelination process.

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Cannabinoids and neuronal damage: Differential effects of THC, AEA and 2-AG on activated microglial cells and degenerating neurons in excitotoxically lesioned rat organotypic hippocampal slice cultures

Cited by 44 publications

References 63 publications

2‐Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal‐cannabidiol‐sensitive receptors on microglial cells

2‐Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal‐cannabidiol‐sensitive receptors on microglial cells

Pretreatment With Electroacupuncture Induces Rapid Tolerance to Focal Cerebral Ischemia Through Regulation of Endocannabinoid System

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

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