Regulating membrane lipid levels at the synapse by small-molecule inhibitors of monoacylglycerol lipase: new developments in therapeutic and PET imaging applications

Grimsey, Natasha L.; Savinainen, Juha R.; Attili, Bala; Ahamed, Muneer

doi:10.1016/j.drudis.2019.10.004

Cited by 18 publications

(11 citation statements)

References 133 publications

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“…In the Silver Steelhead strain, these tissue-overlapping genes encode the DNA nuclease Harbinger transposase derived 1 (HARBI1) [ 31 ] and two proteins involved in the protection against oxidative stress, glutamate cysteine ligase, catalytic subunit (GCLC) [ 32 ] and peroxiredoxin 6 protein (PRDX6) [ 33 ]. In the Born strain, these tissue-overlapping genes encode NLR family CARD domain containing protein 3 (NLRC3), a central negative regulator of the inflammatory immune response [ 34 ] and the monoacylglycerol lipase (MGLL) [ 35 ]. These genes commonly expressed in four tissues are involved in the top three significantly enriched strain- and tissue-specific canonical pathways NRF2-mediated oxidative stress response (head kidney/muscle, p = 2.37 × 10 −4 /4.97 × 10 −4 ) and Glutathione biosynthesis ( p = 2.10 × 10 −4 ) in the Silver Steelhead strain and TREM1 signaling ( p = 1.11 × 10 −4 ) in the Born strain ( Figure 2 a).…”

Section: Resultsmentioning

confidence: 99%

“…containing protein 3 (NLRC3), a central negative regulator of the inflammatory immune response [34] and the monoacylglycerol lipase (MGLL) [35]. These genes commonly expressed in four tissues are involved in the top three significantly enriched strain-and tissue-specific canonical pathways NRF2-mediated oxidative stress response (head kidney/muscle, p = 2.37 × 10 −4 /4.97 × 10 −4 ) and Glutathione biosynthesis (p = 2.10 × 10 −4 ) in the Silver Steelhead strain and TREM1 signaling (p = 1.11 × 10 −4 ) in the Born strain (Figure 2a).…”

Section: A Total Of 1760 Annotated Genes Were Differently Expressed Bmentioning

confidence: 99%

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Comparative Analysis of the Transcriptome and Distribution of Putative SNPs in Two Rainbow Trout (Oncorhynchus mykiss) Breeding Strains by Using Next-Generation Sequencing

Ríos-Pérez

Brunner

Hadlich

et al. 2020

Genes

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Selective breeding can significantly improve the establishment of sustainable and profitable aquaculture fish farming. For rainbow trout (Oncorhynchus mykiss), one of the main aquaculture coldwater species in Europe, a variety of selected hatchery strains are commercially available. In this study, we investigated the genetic variation between the local Born strain, selected for survival, and the commercially available Silver Steelhead strain, selected for growth. We sequenced the transcriptome of six tissues (gills, head kidney, heart, liver, spleen, and white muscle) from eight healthy individuals per strain, using RNA-seq technology to identify strain-specific gene-expression patterns and single nucleotide polymorphisms (SNPs). In total, 1760 annotated genes were differentially expressed across all tissues. Pathway analysis assigned them to different gene networks. We also identified a set of SNPs, which are heterozygous for one of the two breeding strains: 1229 of which represent polymorphisms over all tissues and individuals. Our data indicate a strong genetic differentiation between Born and Silver Steelhead trout, despite the relatively short time of evolutionary separation of the two breeding strains. The results most likely reflect their specifically adapted genotypes and might contribute to the understanding of differences regarding their robustness toward high stress and pathogenic challenge described in former studies.

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Section: Resultsmentioning

confidence: 99%

Section: A Total Of 1760 Annotated Genes Were Differently Expressed Bmentioning

confidence: 99%

Comparative Analysis of the Transcriptome and Distribution of Putative SNPs in Two Rainbow Trout (Oncorhynchus mykiss) Breeding Strains by Using Next-Generation Sequencing

Ríos-Pérez

Brunner

Hadlich

et al. 2020

Genes

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“…Thus, cannabinoid nanoformulations using nanoconjugation strategies for biomedical applications can be considered in attempts to overcome drug delivery challenges to improve bioavailability, safety, diagnosis and efficacy. Specifically, cannabinoid theranostic nanoparticles have translational potential in breast cancer and in targeting components of the ECS in a number of health disorders [10,11].…”

Section: Nanoparticle Cannabinoid Conjugatesmentioning

confidence: 99%

“…Nanotechnology is already transforming multiple facets of drug delivery in healthcare and the future of cannabis and cannabinoid use in nanomedicine offers promising solutions for many disease conditions. While the low aqueous solubility, low cell penetration and susceptibility to degradation of lipophilic cannabinoids present sustained delivery issues, progress in the formulation of targeted cannabinoid-nanocarrier delivery systems using different materials and techniques, provides unique opportunities to protect these compounds from degradation [6,7,10,11]. Many carrier systems have been studied, including liposomes, polymeric micelles, microspheres and nanoparticles and the choice of carrier depends on the molecular target for delivery.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Challenges of Cannabinoid Delivery: How Can Nanomedicine Help?

Onaivi

Chauhan

Sharma

2020

Nanomedicine (Lond.)

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“…Monoacylglycerol lipase (MAGL) is a serine hydrolase highly expressed throughout the brain and is responsible for converting 2-arachidonylglycerol (2-AG) to arachidonic acid (AA) [1,2]. As such, the MAGL hydrolytic activity has an important role regulating endocannabinoid signaling as well as in ammatory responses.…”

Section: Introductionmentioning

confidence: 99%

Target Occupancy Study and Whole-Body Dosimetry with a MAGL PET Ligand 11C-PF-06809247 in non-human Primates

Arakawa

Takano

Nag

et al. 2021

Preprint

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BackgroundMonoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system (CNS). To develop [11C]PF-06809247 into a clinically usable positron emission tomography (PET) radioligand, we assessed the brain target occupancy of a MAGL inhibitor using non-human primate (NHP). Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses.MethodsSeven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a selective MAGL inhibitor, (total of seven doses between 0.01-1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by an irreversible two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. Ki by 2TC and Patlak analysis were calculated. The target occupancy was calculated using Ki at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model.ResultsRadioactivity was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4%-100.5% in a dose dependent manner. Whole-body PET showed high uptake values in the liver, small intestine, kidney, and brain. The effective dose was calculated as 4.3 μSv/MBq.Conclusions[11C]PF-06809247 is a promising PET ligand for further MAGL studies in human brain.

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Regulating membrane lipid levels at the synapse by small-molecule inhibitors of monoacylglycerol lipase: new developments in therapeutic and PET imaging applications

Cited by 18 publications

References 133 publications

Comparative Analysis of the Transcriptome and Distribution of Putative SNPs in Two Rainbow Trout (Oncorhynchus mykiss) Breeding Strains by Using Next-Generation Sequencing

Comparative Analysis of the Transcriptome and Distribution of Putative SNPs in Two Rainbow Trout (Oncorhynchus mykiss) Breeding Strains by Using Next-Generation Sequencing

Challenges of Cannabinoid Delivery: How Can Nanomedicine Help?

Target Occupancy Study and Whole-Body Dosimetry with a MAGL PET Ligand 11C-PF-06809247 in non-human Primates

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