Pharmacology of Acute PainNMDA receptor subunits: Function and pharmacology

A high-throughput screen identifies inhibitors of lung cancer stem cells.

GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[18F]OF-Me-NB1 was reported to be more specific and selective than (S)-[18F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 in nonhuman primates.The radiosynthesis of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 started from 18F-fluorination of the boronic ester precursor, followed by removal of the acetyl protecting group. PET scans in two rhesus monkeys were conducted on the Focus 220 scanner. Blocking studies were performed after treatment of the animals with the GluN2B antagonist Co101,244 or the sigma-1 receptor antagonist FTC-146. One-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method with arterial input function were used to obtain the regional volume of distribution (VT, mL/cm3). Occupancy values by the two blockers were obtained by the Lassen plot. Regional non-displaceable binding potential (BPND) was calculated from the corresponding baseline VT and the VND derived from the occupancy plot of the Co101,244 blocking scans.(R)- and (S)-[18F]OF-Me-NB1 were produced in > 99% radiochemical and enantiomeric purity, with molar activity of 224.22 ± 161.69 MBq/nmol at the end of synthesis (n = 10). Metabolism was moderate, with ~ 30% parent compound remaining for (R)-[18F]OF-Me-NB1 and 20% for (S)-[18F]OF-Me-NB1 at 30 min postinjection. Plasma free fraction was 1-2%. In brain regions, both (R)- and (S)-[18F]OF-Me-NB1 displayed fast uptake with slower clearance for the (R)- than (S)-enantiomer. For (R)-[18F]OF-Me-NB1, both the 1TC model and MA1 method gave reliable estimates of regional VT values, with MA1 VT (mL/cm3) values ranging from 8.9 in the cerebellum to 12.8 in the cingulate cortex. Blocking with 0.25 mg/kg of Co101,244 greatly reduced the uptake of (R)-[18F]OF-Me-NB1 across all brain regions, resulting in occupancy of 77% and VND of 6.36, while 0.027 mg/kg of FTC-146 reduced specific binding by 30%. Regional BPND, as a measure of specific binding signals, ranged from 0.40 in the cerebellum to 1.01 in the cingulate cortex.In rhesus monkeys, (R)-[18F]OF-Me-NB1 exhibited fast kinetics and heterogeneous uptake across brain regions, while the (S)-enantiomer displayed a narrower dynamic range of uptake across regions. A Blocking study with a GluN2B antagonist indicated binding specificity. The value of BPND was > 0.5 in most brain regions, suggesting good in vivo specific binding signals. Taken together, results from the current study demonstrated the potential of (R)-[18F]OF-Me-NB1 as a useful radiotracer for imaging the GluN2B receptors. 

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Characterization in nonhuman primates of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 for imaging the GluN2B subunits of the NMDA receptor

The effect of N1-dansylspermine, a polyamine analogue and competitive polyamine antagonist, and Ro25,6981, a noncompetitive polyamine antagonist with good affinity and selectivity for the GluN2B subunit, on locomotor activity in naive mice was investigated. Furthermore, the ability of the polyamine antagonists to reverse reserpine-induced hypokinesia was assessed, 24 h after injection of a catecholamine-depleting dose of reserpine (5 mg/kg, subcutaneous), to investigate the therapeutic potential of polyamine antagonists in Parkinson's disease. N1-dansylspermine significantly decreased locomotor activity in naive animals (P<0.001) but caused a mild, but significant increase in locomotor activity in reserpinized mice at the highest dose tested (P<0.05). Ro25,6981 significantly stimulated locomotor activity in naive animals (P<0.001) and had a slight significant stimulatory effect on reserpine-induced hypokinesia (P=0.05). N1-dansylspermine and Ro25,6981 had opposite effects on locomotor activity in naive mice, but both had a mild antiparkinsonian effect in the reserpine model. These findings suggest that antagonism of the polyamine binding site on the GluN2B subunit can reduce hypokinesia, albeit to a limited extent.

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Effect of N1-dansylspermine and Ro25,6981 on locomotor activity in naive mice and in the reserpinized mouse model of Parkinson's disease.

Fish is a high-quality animal-source food in the nourishment of millions worldwide. The most edible part of the fish is the muscle and which provides a proper balance of proximate and non-proximate nutrition and has a relatively low caloric value than other meats. The present study aimed to fill the gaps in the nutritional profile of three brackish water fishes (Arius maculatus, Mugil cephalus and Oreochromis niloticus) sourced from Batticaloa Lagoon, Sri Lanka. The study was conducted from November 2019 to February 2020 and fish were sampled from Kallady, Kattankudy and Arayampathy fish markets. The nutritional compositions such as moisture content, protein content, fat content and ash content of epaxial muscles of selected fishes were analyzed with standard methods. The moisture content was high among the fish muscles ranging from 56.73 ± 5.96% to 81.48 ± 2.52%. The protein content of A. maculatus, M. cephalus and O. niloticus muscles ranged as 15.36 ± 1.62%, 17.33 ± 1.96% and 13.7 ± 1.55% respectively. Amidst the selected fishes, O. niloticus is a lean fish (1.27 ± 0.35%) while A. maculatus (3.20 ± 0.59%) and M. cephalus (2.43 ± 0.37%) are low-fat fishes based on the muscle lipid content. The ash content of A. maculatus, M. cephalus and O. niloticus ranged from 1.22 ± 0.15% to 1.77 ± 0.45%, respectively. All the measured proximate parameters were significantly different (P-value &lt; 0.05%) among the three fish species. The results of this study revealed that the A. maculatus contains the highest value of lipid and ash content while O. niloticus contains higher amount of moisture content. The M. cephalus can considered as a good source of animal protein compared to the other two fish species.

http://jsc.sljol.info//articles/10.4038/jsc.v14i5.58/galley/99/download/

Carol Devadasan

Papers

Effect of N1-dansylspermine and Ro25,6981 on locomotor activity in naive mice and in the reserpinized mouse model of Parkinson's disease.

Nutritional composition of three commercially important brackish water fish species recorded from Batticaloa Lagoon, Sri Lanka