Exogenous Anandamide Protects Rat Brain against Acute Neuronal InjuryIn Vivo

Abstract

The endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological magnetic resonance imaging study that exogenously administered AEA dose-dependently reduced neuronal damage in neonatal rats injected intracerebrally with the Na ϩ /K ϩ -ATPase inhibitor ouabain. At 15 min after injury, AEA (10 mg/kg) administered 30 min before ouabain injection reduced the volume of cytotoxic edema by 43 Ϯ 15% in a manner insensitive to the cannabinoid CB 1 receptor antagonist SR141716A. At 7 d after ouabain treatment, 64 Ϯ 24% less neuronal damage was observed in AEA-treated (10 mg/kg) rats compared with control animals. Coadministration of SR141716A prevented the neuroprotective actions of AEA at this end point. In addition, (1) no increase in AEA and 2-arachidonoylglycerol levels was detected at 2, 8, or 24 hr after ouabain injection; (2) application of SR141716A alone did not increase the lesion volume at days 0 and 7; and (3) the AEA-uptake inhibitor, VDM11, did not affect the lesion volume. These data indicate that there was no endogenous endocannabinoid tone controlling the acute neuronal damage induced by ouabain. Although our data seem to question a possible role of the endogenous cannabinoid system in establishing a brain defense system in our model, AEA may be used as a structural template to develop neuroprotective agents.

Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways

“…For example, 2-AG has been shown to reduce edema formation and enhance functional recovery after brain injury in mice. 46 Similarly, neuroprotective effects for anandamide have been reported in a rat model of ouabaininduced acute brain injury, 21 as well as in neuronal cell cultures, where low doses of anandamide (0.1-0.3 mM) protected cells exposed to hypoxia and glucose deprivation. 47 In contrast, we have recently found that anandamide induces neuronal cell loss after intracerebroventricular (icv) injections in rat brain (I Cernak et al, unpublished observation).…”

“…[15][16][17] Endogenous cannabinoids, such as 2-arachidonoyl-glycerol (2-AG), are generally believed to play a neuroprotective role through actions at CB receptors, and anandamide has also been reported to provide neuroprotection through activation of CB receptors. 4,[18][19][20][21] However, in human neuroblastoma CHP100 and lymphoma U937 cell lines, anandamide induces apoptotic cell death through actions at VR1 receptors, leading to caspase activation. 17 In the present studies, we show that anandamide induces dose-dependent cell death in both rat cortical neuronal and cerebellar granule cells.…”

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

“…Cannabinoids and the CB 1 receptor exert neuroprotective effects in response to neurotoxic stimuli. Arvanil, a synthetic AEA analog, acts against ouabain-induced excitotoxicity via CB 1 receptor activation and prevents neuronal cell death in vivo (29). HU210 displays neuroprotective activity against excitotoxicity in a multiple sclerosis model (30).…”

N-Acylethanolamines Are Metabolized by Lipoxygenase and Amidohydrolase in Competing Pathways during Cottonseed Imbibition

“…N-Arachidonylethanolamine (anandamide), a type of NAE in mammalian brain tissue, is an endogenous ligand for the cannabinoid receptor and modulates neurotransmission. Anandamide also can activate vanilloid (capsaicin) receptors and function as an endogenous analgesic (Pertwee, 2001), and appears to be involved in neuroprotection (Hansen et al, 2000;Van der Stelt et al, 2001). In other animal tissues, NAEs have been implicated in immunomodulation (Buckley et al, 2000), synchronization of embryo development (Paria and Dey, 2000), and induction of apoptosis (Sarker et al, 2000).…”