Acute Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Prevents Drug-Induced Heroin Seeking in Rats

Substance use disorder is a difficult disease to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there are currently effective, yet not ideal, treatments to prevent relapse. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin and nicotine. Here, we tested the acute effects of the long-acting GLP-1 analog, liraglutide, on heroin seeking. We found that, in rats with heroin self-administration experience, subcutaneous (sc) administration of an acute dose of 0.3 mg/kg liraglutide was effective in preventing relapse after exposure to three major precipitators: drug-associated cues, stress, and the drug itself. However, the effects of the drug were contingent upon the pretreatment time, with the drug being fully effective when administered using a 6 h, rather than a 4 h pretreatment time. Finally, we confirmed that the reduction in drug seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, this acute non-opioid treatment may serve as a new and effective bridge to treatment.

Activation of cardiac Nmnat/NAD+/SIR2 pathways mediates endurance exercise resistance to lipotoxic cardiomyopathy in aging Drosophila

ABSTRACT Endurance exercise is an important way to resist and treat high-fat diet (HFD)-induced lipotoxic cardiomyopathy, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathway activation mediates endurance exercise-induced resistance to lipotoxic cardiomyopathy. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and the Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO and PGC-1α expression, superoxide dismutase (SOD) activity and NAD+ levels, and it prevented HFD-induced or cardiac Nmnat knockdown-induced cardiac lipid accumulation, malondialdehyde (MDA) content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression also activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knockdown flies. Therefore, the current results confirm that cardiac Nmnat/NAD+/SIR2 pathways are important antagonists of HFD-induced lipotoxic cardiomyopathy. Cardiac Nmnat/NAD+/SIR2 pathway activation is an important underlying molecular mechanism by which endurance exercise and cardiac Nmnat overexpression give protection against lipotoxic cardiomyopathy in Drosophila.

ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival

Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.

Cardiac Nmnat/NAD+/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in aging Drosophila

Endurance exercise is an important way to resist and treat a high-fat-diet(HFD)-induced heart defects, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathways activation could mediate endurance exercise resistance to heart defects. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO, PGC-1α expression, SOD activity, and NAD+ level, and it prevented HFD-induced or cardiac Nmnat knock-down-induced cardiac lipid accumulation, MDA content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knockdown flies. Therefore, current results confirmed that cardiac Nmnat/NAD+/SIR2 pathways were important antagonists of HFD-induced heart defects. The cardiac Nmnat/NAD+/SIR2 pathways activation was the important underlying molecular mechanism of endurance exercise and cardiac Nmnat overexpression against heart defects in Drosophila.

Characterisation of nociception and inflammation observed in a traumatic muscle injury model in rats

Introduction: Muscle pain is the most prevalent type of pain in the world, but treatment remains ineffective. Objective: Therefore, this study characterised the nociception and inflammation in a traumatic muscle injury model in rats Methods: A single blunt trauma impact on the right gastrocnemius muscle of male Wistar rats. Procedures were approved by the Institutional Committee for Animal Use of the Federal University of Santa Maria (#6579280218/2018). Animals were divided into four groups (sham/no treatment; sham/diclofenac 1%; injury/no treatment; injury/diclofenac 1%) and the topical treatment with cream of 1% monosodium diclofenac (applied at 2, 6, 12, 24, and 46 h after muscle injury; 200 mg/muscle) was used as an anti-inflammatory control. Nociception (mechanical and cold allodynia, or nociceptive score) and locomotor activity were evaluated at 26 and 48 h after injury. Also, inflammatory and oxidative parameters were evaluated in gastrocnemius muscle and the creatine kinase (CK) activity and lactate levels in plasma and serum, respectively. Results: Muscle injury caused mechanical and cold allodynia, and increased nociceptive scores, without inducing locomotor impairment. This model also increased the inflammatory cells infiltration (seen by myeloperoxidase and Nacetyl-β-D-glucosaminidase activities and histological procedure), nitric oxide, IL- 1β, IL-6, and dichlorofluorescein levels in muscle samples; and CK activity and lactate levels in serum. The treatment with 1% monosodium diclofenac reduced inflammatory cells infiltration, dichlorofluorescein, and lactate levels. Conclusion: In this view, we characterised the traumatic muscle injury as a reproducible model of muscle pain, which make it possible to evaluate promising antinociceptive and anti-inflammatory therapies.

Aerobic fitness is a potential crucial factor in protecting paralympic athletes with locomotor impairments from atherosclerotic cardiovascular risk

Purpose To test the hypothesis that aerobic fitness is inversely related to the risk of atherosclerotic cardiovascular disease (ACVD) in athletes with locomotor impairments deriving from health conditions, such as spinal cord injury (SCI), lower limb amputation, cerebral palsy, poliomyelitis, and other health conditions different from the previous ones. Methods A total of 68 male athletes who competed in either summer or winter Paralympic games were divided in two health conditions groups (35 with SCI, mean age 37.2 ± 8.0 years, and 33 with different health conditions, mean age 37.8 ± 9.9 years) and in four sport type groups (skill, power, intermittent—mixed metabolism—and endurance). They were evaluated through anthropometric and blood pressure measurements, laboratory blood tests, and graded cardiopulmonary maximal arm cranking exercise test, with oxygen uptake peak (VO2peak) measurement. Cardiovascular risk profile was assessed in each athlete. Results The prevalence of ACVD-risk factors in the overall population was 20.6% for hypertension; 47% and 55.9% for high values of total and LDL cholesterol, respectively; 22.1% for reduce glucose tolerance; and 8.8% for obesity. No difference was found between athletes with and without SCI, while the prevalence of obesity was significantly higher in those practicing skill sports (22.7%, p = 0.035), which was the sport type group with Paralympic athletes with the lowest VO2peak (22.5 ± 5.70 ml kg−1 min−1). VO2peak was lower in athletes with SCI than those with different health conditions (28.6 ± 10.0 vs 33.6 ± 8.9 ml kg−1 min−1p = 0.03), and in those with 3–4 risk factors (19.09 ± 5.34 ml kg−1 min−1) than those with 2 risk factors (27.1 ± 5.50 ml kg−1 min−1), 1 risk factor (31.6 ± 8.55 ml kg−1 min−1), or none (36.4 ± 8.76 ml kg−1 min−1) (p < 0.001). Conclusions The present study suggests that having higher VO2peak seems to offer greater protection against ACVD in individuals with a locomotor impairment. Prescribing physical exercise at an intensity similar to that of endurance and intermittent sports should become a fundamental tool to promote health among people with a locomotor impairment.

Comparison between the 10- and the 30-s-long Wingate Anaerobic Test in summer Paralympic athletes with a lower limb impairment

Background The 30-s-long Wingate Anaerobic Test (WAnT_30s) has some limitations in high-level athletes. A shorter version might be helpful for both clinical applications and performance assessment. The comparison between the traditional WAnT_30s and a shorter version has never been carried out yet in Paralympic athletes. Aim To assess if a 10-s-long Wingate Anaerobic Test (WAnT_10s) could be used to accurately assess and predict the anaerobic components of physical fitness as an alternative to the traditional WAnT_30s in male Paralympic athletes. Methods Forty-four trained male Paralympic Athletes grouped by severity of locomotor impairment completed the WAnT_30s and the WAnT_10s with an arm cranking ergometer. Differences between mean and peak power achieved throughout both WAnTs were analysed using a mixed-design analysis of variance and predictivity was assessed by stepwise linear regression analysis. Results In the whole sample, peak power values were similar (P > 0.005) in the two tests and the WAnT_10s mean power was significantly higher than that in the WAnT_30s (P < 0.005). Finally, the mean power measured during WAnT_30s showed high level of predictability from mean power measured during WAnT_10s and the Functional class (adjusted R2 = 0.906; P < 0.001). Conclusion The WAnT_10s is accurate to assess peak power, is definitively appropriate to evaluate the alactic anaerobic metabolism and seems able to predict the mean power as traditionally evaluated through a WAnT_30s in male Paralympic Athletes. Thus, it can be used to assess the anaerobic components of physical fitness in this athletic population.

Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster

Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration–deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI–induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.