Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation

Abstract

Endocannabinoids are involved in synaptic signaling and neuronal protection; however, our understanding of the mechanisms by which endocannabinoids protect neurons from harmful insults remains elusive. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB 1 and CB 2 ), is a substrate for cyclooxygenase-2 (COX-2) and can be metabolized by COX-2. Here we show, however, that 2-AG is also capable of suppressing elevation of hippocampal COX-2 expression in response to proinflammatory and excitotoxic stimuli. 2-AG prevents neurodegeneration from toxic assaults that elevate COX-2 expression and inhibits the COX-2 elevation-enhanced excitatory glutamatergic synaptic transmission. The action of 2-AG on suppression of COX-2 appeared to be mediated via the pertussis toxin-sensitive G protein-coupled CB 1 receptor and MAPK/NF-B signaling pathways. Our results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COX-2, which provides a mechanistic basis for opening up new therapeutic approaches for protecting neurons from inflammation-and excitotoxicity-induced neurodegeneration. Endocannabinoids (eCBs)2 are endogenous lipid mediators capable of binding to and functionally activating cannabinoid receptors (CB 1 and CB 2 ) to modulate synaptic function and produce neuroprotection (1-10). Although the role of eCBs in synaptic signaling has been investigated extensively, the mechanisms underlying the neuroprotection of eCBs are largely unknown (2, 3). Arachidonoylethanolamide (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), the two most studied eCBs, have been demonstrated to be involved in a variety of physiological and pathological processes (1, 4 -6, 11). Despite their similar chemical structure, however, the production and degradation of 2-AG and AEA are through different pathways (1, 4 -6, 11, 12). 2-AG is produced mainly from diacylglycerol by diacylglycerol lipase and hydrolyzed to arachidonic acid (AA) by monoacylglycerol lipase (MGL), whereas AEA is largely synthesized from N-arachidonoylphosphatidylethanolamine by phospholipase D and degraded to AA by fatty-acid amide hydrolase (FAAH). Moreover, stimulation of glutamate release from Schaffer collaterals in rat hippocampal slices elevates levels of 2-AG but not AEA (13). Both 2-AG and AEA are substrates for cyclooxygenase-2 (COX-2), an inducible enzyme converting AA to classic prostaglandins, and are oxygenated by COX-2 to form new types of prostaglandins: prostaglandin glycerol esters and prostaglandin ethanolamides (14 -18). However, there are differences in COX-2 oxidative metabolism of 2-AG and AEA. For instance, COX-2 efficiently metabolizes 2-AG to prostaglandin glycerol esters as it converts AA to classic prostaglandins, whereas the reaction of COX-2 metabolism of AEA to produce prostaglandin ethanolamides is relatively slow (14, 16). Importantly, AEA is a partial CB 1 and a weak CB 2 agonist, as well as an...

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…19,20,25 Cortical and hippocampal tissues were extracted and immediately homogenized in RIPA lysis buffer and protease inhibitors, and incubated on ice for 30 minutes, then centrifuged for 10 minutes at 10,000 r.p.m. at 4°C.…”

“…The fold increase or decrease was determined relative to naive or sham controls after normalizing to a housekeeping gene using 2 − ΔΔCT , where ΔCT is (gene of interest CT) − (glyceraldehyde-3-phosphate-dehydrogenase CT), and ΔΔCT is (ΔCT treated) − (ΔCT control), as described previously. 19,20,25 Immunohistochemistry Immunohistochemical analyses were performed to determine Aβ, TDP-43, phosphorylated tau, Iba1, and glial fibrillary acidic protein in coronal brain sections as described previously. 19,25 Animals were anesthetized with ketamine/xylazine (200/10 mg/kg) and subsequently transcardially perfused with phosphate-buffered saline followed by 4% paraformaldehyde in phosphate buffer.…”

Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation

“…Evidence has been presented that 2-AG may function as an endogenous inhibitor of cyclooxygenase-2 (COX-2) thereby resulting in a protective effect on neurons that are exposed to harmful insults such as those due to inflammation (82). The mechanism appears to involve COX-2 suppression via the pertussis toxin-sensitive G protein-coupled CB1 receptor and mitogen-activated protein kinases/nuclear factor-B signaling pathways.…”

Negative Regulation of Leptin-induced Reactive Oxygen Species (ROS) Formation by Cannabinoid CB1 Receptor Activation in Hypothalamic Neurons

“…Activation of PPAR-␥ by a specific agonist further enhances catalase activity and protects neurons from oxidative stress (10). Growing evidence indicates that endocannabinoids exhibit profound anti-inflammatory and neuroprotective properties in response to harmful insults, including oxidative stress (11)(12)(13)(14)(15). Some of these effects appear to be mediated by PPAR-␥ activation (16 -18).…”