NAAG Peptidase Inhibitors Act via mGluR3: Animal Models of Memory, Alzheimer's, and Ethanol Intoxication.

Glutamate carboxypeptidase II (GCPII) inactivates the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) following synaptic release. Inhibitors of GCPII increase extracellular NAAG levels and are efficacious in animal models of clinical disorders via NAAG activation of a group II metabotropic glutamate receptor. mGluR2 and mGluR3 knock-out (ko) mice were used to test the hypothesis that mGluR3 mediates the activity of GCPII inhibitors ZJ43 and 2-PMPA in animal models of memory and memory loss. Short- (1.5 h) and long- (24 h) term novel object recognition tests were used to assess memory. Treatment with ZJ43 or 2-PMPA prior to acquisition trials increased long-term memory in mGluR2, but not mGluR3, ko mice. Nine month-old triple transgenic Alzheimer's disease model mice exhibited impaired short-term novel object recognition memory that was rescued by treatment with a NAAG peptidase inhibitor. NAAG peptidase inhibitors and the group II mGluR agonist, LY354740, reversed the short-term memory deficit induced by acute ethanol administration in wild type mice. 2-PMPA also moderated the effect of ethanol on short-term memory in mGluR2 ko mice but failed to do so in mGluR3 ko mice. LY354740 and ZJ43 blocked ethanol-induced motor activation. Both GCPII inhibitors and LY354740 also significantly moderated the loss of motor coordination induced by 2.1 g/kg ethanol treatment. These data support the conclusion that inhibitors of glutamate carboxypeptidase II are efficacious in object recognition models of normal memory and memory deficits via an mGluR3 mediated process, actions that could have widespread clinical applications.

A selective GSK3ß inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice.

Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3ß) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3ß inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3ß inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on ß-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3ß in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

Clinical Use of a Real-World Low Carbohydrate Diet Resulting in Reduction of Insulin Dose, Hemoglobin A1c, and Weight.

Introduction: Type 2 Diabetes Mellitus (T2DM) is increasing in epidemic proportions. In addition to the morbidity and mortality, for those treated with insulin, the physical, psychological, and financial tolls are often greater. Our real-world study evaluated a Low Carbohydrate Diet (LCD) in patients with T2DM on insulin with respect to glycemic control, insulin reduction, and weight loss. Materials and Methods: A prospective cohort study was conducted via an Electronic Medical Record search for patients attending the Virginia Commonwealth University Medical Weight Loss Program from 2014 to 2020 with Type 2 Diabetes Mellitus who initially presented on insulin. Data was extracted for 1 year after enrollment. The weight loss program focuses on a LCD. Results: Of 185 participants, the mean (± SD) age was 56.1 (9.9) years. Seventy percent were female and 63% were black. Eighty-five completed 12 months (45.9%), reduced their median (25-75% interquartile range, IQR) insulin dose from 69 to 0 units (0-18, p < 0.0001), HbA1c from 8 to 6.9% (6.2-7.8, p < 0.0001), and weight from 116 to 99 kg (85-120, p < 001). Eighty six percent who completed 12 months were able to reduce or discontinue insulin, with 70.6% completely discontinuing. Among all participants who completed 3, 6, or 12 months, 97.6% were able to reduce or eliminate insulin use. Conclusion: In patients with T2DM on a LCD, it is possible to reduce and even discontinue insulin use while facilitating weight loss and achieving glycemic control. A Low Carbohydrate Diet should be offered to all patients with diabetes, especially those using insulin.