Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.

The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H₂O₂ and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors 6 (IC₅₀ 0.54 μM, Ki 1.60 μM) and 7 (IC₅₀ 0.23 μM, K_i 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury.

Background and Objectives: Type 2 diabetes is common amongst Bangladeshis, and prevention strategies are needed. Little is known about the views of younger people concerning diabetes prevention and the risk factors. We aimed to explore the experience and views on the prevention of diabetes amongst young Bangladeshis in Tower Hamlets. Methods: Semistructured interviews involving 40 young Bangladeshis. Results: Participants were aware of diabetes being a major health issue and its link with poor diet. Many had a relative with diabetes, and some had negative experiences, such as suffering poor control, complications, or hypoglycemia. Knowledge of diabetes was predominantly gleaned from school. Many felt that older generations were at higher risk due to lack of exercise and reliance on traditional diets. Participants recognized that the Westernized diets also increased the risk of diabetes. Views on prevention of diabetes were strong, including increasing diabetes awareness in schools, rewards for healthier lifestyles, reducing costs of exercise, reducing advertising of poorly nutritious foods, and tackling the proliferation of fast food outlets. Conclusions: Young Bangladeshi people showed good knowledge of diabetes and its causes and have cogent ideas on its prevention. The views of young people should be considered when developing diabetes prevention strategies at the local and national level.