Tetrahydroquinolin-3-yl carbamate glucocorticoid receptor agonists with reduced PEPCK activation.

Continuing studies on tetrahydroquinoline glucocorticoid receptor anti-inflammatory agents lead to the identification of several tetrahydroquinolin-3-yl carbamates that exhibited steroid-like activity in in vitro transrepression assays with reduced transactivation of phosphoenol pyruvate carboxykinase (PEPCK), a key enzyme in the gluconeogenesis pathway.

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Early maternal separation increases symptoms of activity-based anorexia in male and female rats.

Running activates the hypothalamic-pituitary-adrenal (HPA) axis, increasing the release of stress hormones known to exert anorexic effects. HPA axis reactivity is strongly influenced by early postnatal manipulations, including removal of pups from the dam for short (handling) or prolonged (maternal separation) durations during the preweaning period. The authors examined the effects of handling and maternal separation on food intake, body weight loss, and running rates of young adult male and female rats in the activity-based anorexia (ABA) paradigm. Postnatal treatment did not affect adaptation to a 1-hr restricted feeding schedule before the introduction of wheel running. During the ABA paradigm, maternally separated animals lost weight faster, ate less, ran more, and required fewer days to reach removal criterion compared with handled rats. Females were particularly vulnerable. These findings indicate that early postnatal treatment and sex influence ABA.

Sexually dimorphic effects of postnatal treatment on the development of activity-based anorexia in adolescent and adult rats.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a marked feature of anorexia nervosa. Using a modified version of the activity-based animal model of anorexia nervosa, we examine whether factors known to affect HPA axis activity influence the development of activity-based anorexia (ABA). Male and female rats were subjected to maternal separation or handling procedures during the first two postnatal weeks and tested in a mild version of the ABA paradigm, comprised of 2-hr daily running wheel access followed by 1-hr food access, either in adolescence or adulthood. Compared to handled females, maternally separated females demonstrated greater increases in wheel running and a more pronounced running-induced suppression of food intake during adolescence, but not in adulthood. In contrast, it was only in adulthood that wheel running produced more prolonged anorexic effects in maternally separated than in handled males. These findings highlight the interplay between early postnatal treatment, sex of the animal, and developmental age on running, food intake, and rate of body weight loss in a mild version of the ABA paradigm.

Somatosensory stimulation to improve hand and upper limb function after stroke-a systematic review with meta-analyses.

Background Somatosensory stimulation may have a positive impact on recovery of motor function by maintaining cortical representation of the hand and acting to prime the motor system for movement. Objective Determine the efficacy of somatosensory stimulation on upper limb motor function after stroke. Methods Five electronic databases (MEDLINE, CINAHL, Embase, PEDro and OT Seeker) were searched from inception to October 2016. Included studies were English-language randomized controlled trials where a sensory intervention was applied below the elbow to improve upper limb motor control of adults after stroke. One outcome needed to measure arm function at an impairment or activity level. Study selection and quality assessment (using the PEDro scale) were independently conducted by two reviewers. Meta-analysis was completed where there was sufficient homogeneity between trials. Results Fifteen articles were included reporting data from 14 randomized controlled trials (627 participants). There was low-quality evidence from four trials that sensory electrical stimulation did not improve upper limb activity compared to placebo (SMD 0.4, 95%CI -0.07 to 0.87, I2 38%) and moderate-quality evidence from three trials that it did not improve motor impairment (MD 3.45 units, 95%CI -1.47 to 8.36, I2 35%). Low-quality evidence from two trials demonstrated that therapist-delivered sensory stimulation did not improve upper limb activity (SMD 0.25, 95%CI -0.20 to 0.69, I2 0%) compared to usual care. Conclusion Current low- to moderate-quality evidence suggests somatosensory stimulation is not effective in improving upper limb motor impairment or activity after stroke.

Prior experience with wheel running produces cross-tolerance to the rewarding effect of morphine.

The rewarding effect of wheel running is hypothesized to be mediated by endogenous opioids. Thus, prior experience with wheel running might be expected to affect the reward value of an opiate drug like morphine. In three similar experiments to test this idea, 10 rats (wheel-morphine group) were confined in running wheels for 2 h on each of eight consecutive days during the first phase; the 10 in the cage-morphine group were confined in small metal cages. Then, in the second phase, a distinctive place was paired with morphine (1 mg/kg) on three occasions to produce conditioned place preference (CPP). In all experiments, CPP occurred in the cage-morphine group, but not in the wheel-morphine group, implying that prior wheel running resulted in cross-tolerance to the rewarding effect of morphine. This finding supports the idea that the rewarding effect of wheel running is mediated by endogenous opioids.

Single rapamycin administration induces prolonged downward shift in defended body weight in rats.

Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

Dissociation of conditioned taste avoidance from conditioned disgust reactions induced by wheel running in rats.

It is well established that wheel running in rats produces conditioned taste avoidance; that is, rats that run in wheels after consuming a novel-tasting solution later consume less of that solution than rats that do not run. In experiment 1, we found that wheel running also produces conditioned disgust reactions, indicated by gapes elicited by both the taste and context that were experienced before running. Experiment 2 showed that the conditioned disgust reactions were likely not due to running itself but to a by-product of running, the rocking of the wheel that occurs when the running stops. When rocking was reduced, the disgust reactions were also reduced, but consumption of the taste solution was not changed, showing dissociation of conditioned taste avoidance and disgust. These findings indicate that the taste avoidance induced by wheel running itself is more like the taste avoidance produced by rewarding drugs than that produced by nausea-inducing drugs.