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, Despina; Spyridakos, Dimitris; Tzatzarakis, Manolis; Papadogkonaki, Sofia; Filidou, Eirini; Arvanitidis, Konstantinos; Kolios, George; Lamani, Manjunath; Makriyannis, Alexandros; Malamas, Michael S.; Thermos, Kyriaki

doi:10.1016/j.neuropharm.2021.108450

Cited by 15 publications

(23 citation statements)

References 87 publications

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“…Alternatively, differences in excitotoxicity and cell death that occur with activating or inhibiting eCB‐signaling may result from differences in targeting NMDA versus AMPA receptors to elicit neuronal damage. For example, Kokona et al (2021) reported the death of photoreceptors with AMPA‐selective agonists, which does not occur with NMDA. In other disease models where 2‐AG provides neuroprotection the cellular damage and death is slow and progressive (Centonze et al, 2007), unlike our model of NMDA‐induced excitotoxicity where the cellular damage and death are acute and severe.…”

Section: Discussionmentioning

confidence: 99%

“…eCBs have been shown to provide neuroprotection in degenerative retinal diseases (Rapino et al, 2018). Recent articles have even suggested that 2‐AG can mediate neuroprotection against AMPA toxicity in the rat retina (Kokona et al, 2021). We investigated eCB‐related neuroprotection because levels of retinal damage and cell death are known to influence the formation of MGPCs.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, differences in excitotoxicity and cell death that occur with activating or inhibiting eCB-signaling may result from differences in targeting NMDA versus AMPA receptors to elicit neuronal damage. For example, Kokona et al (2021) (Fischer et al, 2002(Fischer et al, , 2014. In addition, FGF2 is potently neuroprotective against NMDA-induced excitotoxicity, and despite decreases in cell death there are increases numbers of proliferating MGPCs (Fischer et al, 2009).…”

Section: Ecbs Are Not Neuroprotective To Excitotoxic Retinal Damagementioning

confidence: 99%

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Cannabinoid signaling promotes the de‐differentiation and proliferation of Müller glia‐derived progenitor cells

Campbell

Blum

Reske

et al. 2021

Glia

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Endocannabinoids (eCB) are lipid‐based neurotransmitters that are known to influence synaptic function in the visual system. eCBs are also known to suppress neuroinflammation in different pathological states. However, nothing is known about the roles of the eCB system during the transition of Müller glia (MG) into proliferating progenitor‐like cells in the retina. Accordingly, we used the chick and mouse model to characterize expression patterns of eCB‐related genes and applied pharmacological agents to investigate how the eCB system impacts glial reactivity and the capacity of MG to become Müller glia‐derived progenitor cells (MGPCs). We queried single cell RNA‐seq libraries to identify eCB‐related genes and identify cells with dynamic patterns of expression in damaged retinas. MG and inner retinal neurons expressed the eCB receptor CNR1, as well as enzymes involved in eCB metabolism. In the chick, intraocular injections of cannabinoids, 2‐Arachidonoylglycerol (2‐AG) and Anandamide (AEA), stimulated the formation of MGPCs. Cannabinoid Receptor 1 (CNR1)‐agonists and Monoglyceride Lipase‐inhibitor promoted the formation of MGPCs, whereas CNR1‐antagonist and inhibitors of eCB synthesis suppressed this process. In damaged mouse retinas where MG activate NFkB‐signaling, activation of CNR1 decreased and inhibition of CNR1 increased NFkB, whereas levels of neuronal cell death were unaffected. Surprisingly, retinal microglia were largely unaffected by increases or decreases in eCB‐signaling in both chick and mouse retinas. We conclude that the eCB system in the retina influences the reactivity of MG and the formation of proliferating MGPCs, but does not influence the reactivity of immune cells in the retina.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ecbs Are Not Neuroprotective To Excitotoxic Retinal Damagementioning

confidence: 99%

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Cannabinoid signaling promotes the de‐differentiation and proliferation of Müller glia‐derived progenitor cells

Campbell

Blum

Reske

et al. 2021

Glia

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“…In 2021, a study about the role of 2-AG protection of the retina against the excitatory amino acid AMPA involved two ABHD6 inhibitors: AM12100 which was selective for ABHD6 (IC 50 = 8 nM) and AM11920 which was a dual MAGL and ABHD6 inhibitor (IC 50 values of 12.1 and 6.0 nM, respectively). 135 The structures of both inhibitors are not disclosed yet. Interestingly, both compounds exerted a neuroprotective effect in the animal retinal model of AMPA excitotoxicity, but the selective ABHD6 inhibitor was less effective, thus leading to the conclusion that the dual inhibition exerted by AM11920 induced a more evident 2-AG increase and therefore it showed a better pharmacological profile.…”

Section: Abhd6mentioning

confidence: 99%

Section: Abhd6mentioning

confidence: 99%

α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

et al. 2021

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Much of the experimental evidence in the literature has linked altered lipid metabolism to severe diseases such as cancer, obesity, cardiovascular pathologies, diabetes, and neurodegenerative diseases. Therefore, targeting key effectors of the dysregulated lipid metabolism may represent an effective strategy to counteract these pathological conditions. In this context, α/β-hydrolase domain (ABHD) enzymes represent an important and diversified family of proteins, which are involved in the complex environment of lipid signaling, metabolism, and regulation. Moreover, some members of the ABHD family play an important role in the endocannabinoid system, being designated to terminate the signaling of the key endocannabinoid regulator 2-arachidonoylglycerol. This Perspective summarizes the research progress in the development of ABHD inhibitors and modulators: design strategies, structure–activity relationships, action mechanisms, and biological studies of the main ABHD ligands will be highlighted.

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Design and Synthesis of Highly Potent and Specific ABHD6 Inhibitors

et al. 2021

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Fine‐tuning than complete disruption of 2‐arachidonoylglycerol (2‐AG) metabolism in the brain represents a promising pharmacological approach to limit potential untoward effects associated with complete blockade of monoacylglycerol lipase (MGL), the primary hydrolase of 2‐AG. This could be achieved through a/b‐hydrolase domain containing 6 (ABHD6) inhibition, which will provide a smaller and safer contribution to 2‐AG regulation in the brain. Pharmacological studies with ABHD6 inhibitors have recently been reported, where modulation of ABHD6 activity either through CB1R‐dependent or CB1R‐independent processes showed promise in preclinical models of epilepsy, neuropathic pain and inflammation. Furthermore in the periphery, ABHD6 modulates 2‐AG and other fatty acid monoacylglycerols (MAGs) and is implicated in Type‐2 diabetes, metabolic syndrome and potentially other diseases. Herein, we report the discovery of single‐digit nanomolar potent and highly specific ABHD6 inhibitors with >1000‐fold selectivity against MGL and FAAH. The new ABHD6 inhibitors provide early leads to develop therapeutics for neuroprotection and the treatment of inflammation and diabetes.

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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

Cited by 15 publications

References 87 publications

Cannabinoid signaling promotes the de‐differentiation and proliferation of Müller glia‐derived progenitor cells

Cannabinoid signaling promotes the de‐differentiation and proliferation of Müller glia‐derived progenitor cells

α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

Design and Synthesis of Highly Potent and Specific ABHD6 Inhibitors

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