Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.
The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons. Our previous work with this model suggests that small molecule ligands of the sigma 2 receptor (σ2R), which was recently cloned and identified as transmembrane protein 97 (TMEM97), are neuroprotective. To determine structure–activity relationships for unexplored chemical space in our σ2R/Tmem97 ligand collection, we developed an in vivo high-content screening (HCS) assay to identify potential drug leads. The HCS assay uses our recently developed large-scale microfluidic immobilization chip and automated imaging platform. We discovered norbenzomorphans that reduced neurodegeneration in our C. elegans model, including two compounds that demonstrated significant neuroprotective activity at multiple doses. These findings provide further evidence that σ2R/Tmem97-binding norbenzomorphans may represent a new drug class for treating neurodegenerative diseases.
BACKGROUND Platelet dysfunction (PD) is an independent predictor of mortality in patients with severe traumatic brain injury (sTBI). Platelet transfusions (PLTs) have been shown to be an effective treatment strategy to reverse platelet inhibition. Their use is contingent on availability and may be associated with increased cost and transfusion-related complications, making desmopressin (DDAVP) attractive. We hypothesized that DDAVP would correct PD similarly to PLTs in patients with sTBI. METHODS This retrospective study evaluated all blunt trauma patients admitted to an urban, level 1 trauma center from July 2015 to October 2016 with sTBI (defined as head abbreviated injury scale [AIS] ≥3) and PD (defined as adenosine diphosphate [ADP] inhibition ≥60% on thromboelastography) and subsequently received treatment. Per our institutional practice, patients with sTBI and PD are transfused one unit of apheresis platelets to reverse inhibition. During a platelet shortage, we interchanged DDAVP for the initial treatment. Patients were classified as receiving DDAVP or PLT based on the initial treatment. RESULTS A total of 57 patients were included (DDAVP, n = 23; PLT, n = 34). Patients who received DDAVP were more severely injured (injury severity score, 29 vs. 23; p = 0.045), but there was no difference in head AIS (4 vs. 4, p = 0.16). There was no difference between the two groups in admission platelet count (244 ± 68 × 103/μL vs. 265 ± 66 × 103/μL, p = 0.24) or other coagulation parameters such as prothrombin time, partial thromboplastin time, or international normalized ratio. Before treatment, both groups had similar ADP inhibition as measured by thromboelastography (ADP, 86% vs. 89%, p = 0.34). After treatment, both the DDAVP and PLT groups had similar correction of platelet ADP inhibition (p = 0.28). CONCLUSION In patients with severe traumatic brain injury and PD, DDAVP may be an alternative to PLTs to correct PD. LEVEL OF EVIDENCE Therapeutic, level IV.
Urologic trauma is a well-known cause of urethral injury with a range of management recommendations. Retrograde urethrogram remains the preferred initial diagnostic modality to evaluate a suspected urethral injury. The management thereafter varies based on mechanism of injury. Iatrogenic urethral injury is often caused by traumatic catheterization and is best managed by an attempted catheterization performed by an experienced clinician or suprapubic catheter to maximize urinary drainage. Penetrating trauma, most commonly associated with gunshot wounds, can cause either an anterior and/or posterior urethral injury and is best treated with early operative repair. Blunt trauma, most commonly associated with straddle injuries and pelvic fractures, can be treated with either early primary endoscopic realignment or delayed urethroplasty after suprapubic cystostomy. With any of the above injury patterns and treatment options, a well thought out and regimented follow-up with a urologist is of utmost importance for accurate assessment of outcomes and appropriate management of complications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.