The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons.

Skaper, Stephen D.; Buriani, Alessandro; Toso, Roberto Dal; Petrelli, Lucía; Romanello, Stefano; Facci, Laura; Leon, Alberta

doi:10.1073/pnas.93.9.3984

Cited by 358 publications

(240 citation statements)

References 47 publications

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“…In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 79%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

310

353

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Cannabinoid CB 2 receptors (CB 2 Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB 2 Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB 2 mRNA and CB 2 R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB 2 Rs by JWH133 or other CB 2 R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB 1 −/− mice are blocked by CB 2 R antagonist and absent in CB 2 −/− mice. These data suggest that CB 2 R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.T he presence of functional cannabinoid CB 2 receptors (CB 2 Rs) in the brain has been controversial. When CB 2 Rs were first cloned, in situ hybridization (ISH) failed to detect CB 2 mRNA in brain (1). Similarly, Northern blot and polymerase chain reaction (PCR) assays failed to detect CB 2 mRNA in brain (2-5). Therefore, CB 2 Rs were considered "peripheral cannabinoid receptors" (1, 6).In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21). A currently accepted view is that brain CB 2 Rs are expressed predominantly in activated microglia during neuroinflammation, whereas brain neurons, except for a very small number in the brainstem, lack CB 2 R expression (21).On the other hand, we recently reported that brain CB 2 Rs modulate cocaine self-administration and cocaine-induced increases in locomotion and extracellular dopamine (DA) in the nucleus accumbens in mice (22). This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behav...

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mentioning

confidence: 79%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

310

353

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“…Anandamide (arachidonoylethanolamide, AEA) and its analogue palmitoylethanolamide (PEA) regulate many of the same pathophysiological processes, including pain perception, convulsions, neurotoxicity and inflammation (Calignano et al 1998;Lo Verme et al 2005;Jaggar et al 1998;Lambert et al 2001;Skaper et al 1996). They both fulfill the three criteria required to be considered bona fide lipid transmitters: stimulus-dependent production, interaction with specific receptors and enzymatic inactivation.…”

Section: Introductionmentioning

confidence: 99%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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Microglial cell activation and migration play an important role in neuroinflammation propagation. While it is known that the lipid transmitter palmitoylethanolamide (PEA) regulates microglial migration by interacting with a cannabinoid-like receptor, the production and inactivation of this lipid by microglia has never been addressed directly. Here we show that the mouse microglial cell line BV-2 produces and hydrolyzes PEA. The carbamate compound URB602 inhibits PEA hydrolysis in BV-2 cell homogenates and increases PEA levels in intact cells, whereas the FAAH inhibitor URB597 and serine-hydrolase inhibitor MAFP do not affect PEA levels in intact cells. This unique pharmacological profile of inhibitors on PEA hydrolysis suggests the involvement of a previously undescribed enzyme that degrades PEA. This enzyme expressed by microglia constitutes a promising target for controlling the propagation of neuroinflammation.

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“…N-Palmitoylethanolamine has anti-inflammatory (13)(14)(15), anti-nociceptive (16,17), immunosuppressive (18), neuroprotective (19), and antioxidant (20) effects. Recently, it was shown that the anti-inflammatory action of N-palmitoylethanolamine could be mediated by the activation of peroxisome proliferator-activated receptor-␣ (PPAR-␣) (21).…”

mentioning

confidence: 99%

Molecular Characterization of N-Acylethanolamine-hydrolyzing Acid Amidase, a Novel Member of the Choloylglycine Hydrolase Family with Structural and Functional Similarity to Acid Ceramidase

Tsuboi

Sun

Okamoto

et al. 2005

Journal of Biological Chemistry

298

287

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Bioactive N-acylethanolamines, including anandamide (an endocannabinoid) and N-palmitoylethanolamine (an anti-inflammatory and neuroprotective substance), are hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase. Moreover, we found another amidohydrolase catalyzing the same reaction only at acidic pH, and we purified it from rat lung (Ueda, N., Yamanaka, K., and Yamamoto, S. (2001) J. Biol. Chem. 276, 35552-35557). Here we report complementary DNA cloning and functional expression of the enzyme termed "N-acylethanolamine-hydrolyzing acid amidase (NAAA)" from human, rat, and mouse. The deduced primary structures revealed that NAAA had no homology to fatty acid amide hydrolase but belonged to the choloylglycine hydrolase family. Human NAAA was essentially identical to a gene product that had been noted to resemble acid ceramidase but lacked ceramide hydrolyzing activity. The recombinant human NAAA overexpressed in HEK293 cells hydrolyzed various N-acylethanolamines with N-palmitoylethanolamine as the most reactive substrate. Most interestingly, a very low ceramide hydrolyzing activity was also detected with NAAA, and N-lauroylethanolamine hydrolyzing activity was observed with acid ceramidase. By the use of tunicamycin and endoglycosidase, NAAA was found to be a glycoprotein. Furthermore, the enzyme was proteolytically processed to a shorter form at pH 4.5 but not at pH 7.4. Expression analysis of a green fluorescent protein-NAAA fusion protein showed a lysosome-like distribution in HEK293 cells. The organ distribution of the messenger RNA in rats revealed its wide distribution with the highest expression in lung. These results demonstrated that NAAA is a novel N-acylethanolamine-hydrolyzing enzyme that shows structural and functional similarity to acid ceramidase.

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The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons.

Abstract: The amino acid L-glutamate is a neurotransmitter that mediates

Cited by 358 publications

References 47 publications

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Microglia produce and hydrolyze palmitoylethanolamide

Molecular Characterization of N-Acylethanolamine-hydrolyzing Acid Amidase, a Novel Member of the Choloylglycine Hydrolase Family with Structural and Functional Similarity to Acid Ceramidase

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The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons.

Abstract: The amino acid L-glutamate is a neurotransmitter that mediates

Cited by 358 publications

References 47 publications

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Microglia produce and hydrolyze palmitoylethanolamide

Molecular Characterization of N-Acylethanolamine-hydrolyzing Acid Amidase, a Novel Member of the Choloylglycine Hydrolase Family with Structural and Functional Similarity to Acid Ceramidase

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Product

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Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice