Title : The endocannabinoid 2-arachidonoylglycerol and dual ABHD6\/MAGL enzyme inhibitors display neuroprotective and anti-inflammatory actions in the in vivo retinal model of AMPA excitotoxicity - Kokona_2021_Neuropharmacol_185_108450 |
Author(s) : Kokona D , Spyridakos D , Tzatzarakis M , Papadogkonaki S , Filidou E , Arvanitidis KI , Kolios G , Lamani M , Makriyannis A , Malamas MS , Thermos K |
Ref : Neuropharmacology , 185 :108450 , 2021 |
Abstract :
The endocannabinoid system has been shown to be a putative therapeutic target for retinal disease. Here, we aimed to investigate the ability of the endocannabinoid 2-arachidonoylglycerol (2-AG) and novel inhibitors of its metabolic enzymes, alpha/beta-hydrolase domain-containing 6 (ABHD6) and monoacylglycerol lipase (MAGL), a) to protect the retina against excitotoxicity and b) the mechanisms involved in the neuroprotection. Sprague-Dawley rats, wild type and Akt2(-/-) C57BL/6 mice were intravitreally administered with phosphate-buffered saline or (RS)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA). 2-AG was intravitreally co-administered with AMPA in the absence and presence of AM251 or AM630 (cannabinoid 1 and 2 receptor antagonists, respectively) or Wortmannin [Phosphoinositide 3-Kinase (PI3K)/Akt inhibitor]. Inhibitors of ABHD6 and dual ABHD6/MAGL (AM12100 and AM11920, respectively) were co-administered with AMPA intravitreally in rats. Immunohistochemistry was performed using antibodies raised against retinal neuronal markers (bNOS), microglia (Iba1) and macroglia (GFAP). TUNEL assay and real-time PCR were also employed. The CB2 receptor was expressed in rat retina (approx. 62% of CB1 expression). 2-AG attenuated the AMPA-induced increase in TUNEL(+) cells. 2-AG activation of both CB1 and CB2 receptors and the PI3K/Akt downstream signaling pathway, as substantiated by the use of Akt2(-/-) mice, afforded neuroprotection against AMPA excitotoxicity. AM12100 and AM11920 attenuated the AMPA-induced glia activation and produced a dose-dependent partial neuroprotection, with the dual inhibitor AM11920 being more efficacious. These results show that 2-AG has the pharmacological profile of a putative therapeutic for retinal diseases characterized by neurodegeneration and neuroinflammation, when administered exogenously or by the inhibition of its metabolic enzymes. |
PubMedSearch : Kokona_2021_Neuropharmacol_185_108450 |
PubMedID: 33450278 |
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6 |
Substrate | 2-Arachidonylglycerol |
Gene_locus | human-ABHD6 mouse-ABHD6 |
Kokona D, Spyridakos D, Tzatzarakis M, Papadogkonaki S, Filidou E, Arvanitidis KI, Kolios G, Lamani M, Makriyannis A, Malamas MS, Thermos K (2021)
The endocannabinoid 2-arachidonoylglycerol and dual ABHD6\/MAGL enzyme inhibitors display neuroprotective and anti-inflammatory actions in the in vivo retinal model of AMPA excitotoxicity
Neuropharmacology
185 :108450
Kokona D, Spyridakos D, Tzatzarakis M, Papadogkonaki S, Filidou E, Arvanitidis KI, Kolios G, Lamani M, Makriyannis A, Malamas MS, Thermos K (2021)
Neuropharmacology
185 :108450