bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Peripherally Selective CB1 Receptor Inverse Agonist Improves Metabolic Syndrome in Mice
Authors: Khan Nayaab S , Amato George , Vasukuttan Vineetha , Wang Shaobin , Snyder Rodney , Rosa Taylor , Wiethe Robert , Hackney Aliah , Runyon Scott , Maitra Rangan 
Published: June 2021

The type 1 cannabinoid receptor (CB1) can be targeted to treat major diseases like type 2 diabetes, fibrosis and steatohepatitis. This has led to the development and profiling of several CB1 antagonists; one such drug being rimonabant, a CNS penetrating inverse agonist, for the treatment of obesity. However, rimonabant was discontinued due to CNS‐related adverse psychiatric effects in a subset of patients. Accumulating evidence indicates that peripheral blockade of CB1 with antagonists that have limited brain penetration is an attractive strategy to treat various disorders. Our research has identified RTI‐1092663, a peripherally selective purine‐based inverse agonist with limited brain penetration (~1% of plasma concentration) and good ADME properties, as a therapeutic agent for the treatment of metabolic syndrome. C57/BL6J male mice were fed a standard chow or high fat diet (60% fat calories) from 6 – 24 weeks and were administered vehicle or RTI‐1092663 at doses of 0.1, 0.3 or 1.0mg/kg, PO/day from weeks 20–24. Oral glucose tolerance test was performed 3 days prior to euthanasia. High fat diet (HFD) significantly increased body weight, liver weights and blood glucose levels in both fasted and fed states. HFD also increased hepatic mRNA expression of CXCR1. Treatment with RTI‐1092663 resulted in a significant decline in body weight and liver weight. Further, RTI‐1092663 treatment lowered fasting glucose levels and demonstrated a dose dependent improvement in glucose tolerance. This compound also inhibited increased neutrophil infiltration as demonstrated by a significant decline in CXCR1 mRNA expression. These data suggest that compound RTI‐1092663 could be further developed for the treatment of metabolic syndrome and other diseases.Support or Funding Information1R01AA023256‐011R01DK100414‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mitochondrial Oxidative Metabolism and Dopamine Neurodegeneration in the Mesolimbic Pathway after Prolonged Methamphetamine Self‐Administration in Mice
Authors: Lopez Sergio Dominguez , Ahn Bumsoo , Premkumar Pavithra , Van Remmen Holly , Beckstead Michael J. 
Published: June 2021

The dopaminergic mesolimbic pathway mediates the reinforcing properties of methamphetamine. Postmortem and brain imaging studies indicate that chronic methamphetamine users develop injury and neurodegeneration in the brain structures that form part of this pathway. Moreover, methamphetamine exposure produces an increase of oxidative molecules derived from increased release and metabolism of dopamine, which in turn is thought to initiate an imbalance of the redox metabolism in the mesolimbic pathway. Here we use a model of methamphetamine self‐administration in mice to determine how the oxidative environment produced by chronic methamphetamine exposure affects 1) mitochondrial oxygen consumption rate (OCR) and redox balance of the antioxidant molecule glutathione (GSH) in the ventral tegmental area (VTA) and striatum and, 2) electrophysiological function and survival of dopamine neurons in the VTA. Adult mice were implanted with a jugular catheter and were trained to nose poke to self‐administer methamphetamine in operant chambers in daily two hours sessions. Mice were trained with a schedule that gradually increased the number of nose pokes required to receive an infusion of methamphetamine from a fixed ratio (FR) 1 to a FR3. After training was complete, mice were placed in a FR3 schedule to complete 35–40 days of total methamphetamine self‐administration exposure. Our results showed that drug‐seeking behavior, evaluated with a progressive ratio protocol, was enhanced after 20 days of methamphetamine self‐administration exposure. Using high resolution respirometry and HPLC we detected an increase of mitochondrial OCR accompanied by a decrease of GSH levels in the VTA. Conversely, GSH levels were decreased in the striatum. A decrease in dopamine neuron firing rate and an increase of cell excitability was also detected in whole cell recordings in VTA slices. The number of immunoreactive tyrosine hydroxylase positive neurons was also decreased in the VTA. Our results suggest that prolonged methamphetamine self‐administration exposure produces an oxidative environment along the mesolimbic pathway that affects dopamine neurotransmission and dopamine cell survival in the VTA. The results are consistent with increased oxidative damage in VTA dopamine neurons contributing to neurodegeneration of the mesolimbic pathway and to the development of drug‐seeking behavior with prolonged methamphetamine exposure.Support or Funding InformationThis project was supported by National Institutes of Health Grants R01 DA32701 and AG52606 to MJBThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Green Apple Tobacco Flavorant Farnesol Enhances Nicotine Reward‐related Behavior
Authors: Avelar Alicia Jo , Akers Austin T , Cooper Skylar Y , Baumgard Zack J , Henderson Brandon J 
Published: June 2021

Previous investigations have shown that menthol, the most popular tobacco flavor, can enhance nicotine reward and reinforcement. With the growing popularity of electronic nicotine delivery systems, more flavors are available to smokers and there is a critical need to understand how these flavors may alter nicotine's actions. In this study we examined the green apple flavorant and odorant farnesol for its ability to alter nicotine reward‐related behavior and nicotinic acetylcholine receptor (nAChR) upregulation.Using a conditioned place preference assay we found that farnesol enhanced nicotine reward‐related behavior to a degree that is similar to menthol. When we examined farnesol alone, we observed significant reward‐related behavior. We then used confocal microscopy and α4‐ mCherryα6‐GFP mice to examine the upregulation of α4‐containing (α4*), α6*, and α4α6* nAChRs in ventral tegmental area (VTA) dopamine neurons. Here, we observed that farnesol, by itself, enhanced the upregulation of α6* nAChRs but had little effect on α4* nAChRs.Together, these data show that farnesol alters nicotine reward‐related behavior. This is most likely accomplished by its ability to enhance α6* nAChR upregulation. These data highlight the need to study how tobacco flavors alter nicotine reward and reinforcement.Support or Funding InformationSupport: Marshall University Research Corporation and National Institutes of Health: DA040047 and DA043665 (BJH).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intermittent dietary fish oil supplementation prevents high fat diet‐induced enhanced sensitivity to the behavioral effects of quinpirole
Authors: Beltran Nina M , Galindo Kayla I , Echeverri Jose , Hernandez‐Casner Caroline , Serafine Katherine M 
Published: June 2021

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat laboratory chow are more sensitive than rats eating standard chow to the behavioral effects of dopaminergic drugs. Specifically, drugs that act on dopamine systems (e.g., quinpirole and cocaine) produce unconditioned behavioral effects (e.g., yawning and locomotion) that are enhanced among rats eating high fat chow. Daily dietary supplementation with fish oil prevents this high fat diet‐induced effect; however, doctors recommend that patients take fish oil only 2–3 times a week for beneficial health effects. To test the hypothesis that intermittent (e.g., 2/7 days per week) dietary supplementation with fish oil prevents high fat diet‐induced effects (e.g., enhanced sensitivity to the behavioral effects of dopaminergic drugs) rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), or standard or high fat chow with 20% (w/w) intermittent (e.g., 2/7 days per week) dietary fish oil supplementation were tested once weekly with quinpirole (0.0032–0.32 mg/kg, i.p.) or cocaine (1–17.8 mg/kg, i.p.) using cumulative dosing procedures. Sensitivity to the behavioral effects of quinpirole was enhanced among rats eating high fat chow as compared to rats eating standard chow, and rats eating high fat chow with intermittent dietary fish oil supplementation were protected against this enhanced sensitivity. Intermittent access to fish oil significantly decreased cocaine‐induced locomotion in some groups, without impacting general locomotor activity (e.g., motor activity following saline injections). Future experiments will focus on understanding the mechanism(s) by which fish oil produces beneficial effects, by examining the specific omega‐3 polyunsaturated fatty acids found in fish oil.Support or Funding InformationNina Beltran is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under the linked award number R25GM069621.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dendrobium nobile Lindl. alkaloids decreases the level of intracellular β‐amyloid by improving impaired autolysosomal proteolysis in APP/PS1 mice
Authors: Nie Jing , Jiang Lingshan , Lu Yanliu , Shi Jingshan 
Published: June 2021

As the major degradation pathway for long‐lived proteins and organelles, macroautophagy is a decisive factor for the survival and longevity of cells. The existing evidence indicates that the disruption of substrate proteolysis in autolysosomes is the main mechanism underlying autophagy failure in Alzheimer's disease (AD). Thus, the restoration of normal lysosomal proteolysis and autophagy efficiency is a novel therapeutic strategy in the treatment of AD. In this study, 9‐month‐old APPswe/PS1ΔE9 transgenic (APP/PS1) mice were administered Dendrobium nobile Lindl. alkaloids (DNLA, 40 and 80 mg/kg) or Metformin (80 mg/kg), and age‐matched wild‐type mice were administered an isovolumic vehicle orally once a day for 4 months. The results demonstrated that DNLA significantly improved learning and memory in APP/PS1 transgenic mice in the Morris water maze. Furthermore, DNLA could increase the expression of the v‐ATPase A1 subunit to facilitate lysosomal acidification, prompt the dissociation of the cation independent‐mannose‐phosphate receptor from cathepsin (cat) D, promote the proteolytic maturation of cat D, increase the degradation of accumulated autophagic vacuoles (AVs) and β‐amyloid (Aβ) contained in the AVs, and alleviate neuronal and synaptic injury. These findings demonstrate that DNLA improves learning and memory function in APP/PS1 mice, and the mechanisms appear to be due to the promotion of intracellular Aβ degradation by increasing the protein level of v‐ATPase A1 and then improving autolysosomal acidification and proteolysis.Support or Funding InformationThis work has been supported by the National Natural Science Foundation of China (Grant No. 81473201); Fund of Key Discipline Construction of Zunyi Medical University; Science and Technology Foundation of State Administration of Traditional Chinese Medicine of Guizhou Province (QZYY2017‐016).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
SMU‐A inhibits Aβ‐induced NLRP3 inflammasome via autophagy mediated by the AMPK/ULK1 and Raf/MEK/ERK pathways in microglia
Authors: Anguo Wu , Ya Zhao , Wenqiao Qiu , Jinfeng Teng , Rui Xiong , Jianming Wu , Dalian Qin 
Published: June 2021

Accumulation of β‐amyloid (Aβ) and its induced inflammation are recognized as two major pathological features of Alzheimer disease (AD). Autophagy, an intracellular catabolic mechanism, plays a pivotal role in neurodegenerative disease for degrading the toxic aggregated proteins such as Aβ, α‐Synuclein and mHtt. Recently, autophagy activation in microglia was reported to not only degrade extracellular Aβ fribils but also inhibit Aβ‐induced NLRP3 inflmmasome. In the present experiment, the potential autophagy inducers from SMU, a traditional Chinese medicine, were identified in microglial cells (BV‐2) by using column chromatography, UHPLC‐TOF/MS and NMR technologies. Total four ellagitannin flavonoids including SMU‐A, SMU‐B, SMU‐C and SMU‐D were identified, and SMU‐A was proved to possess the best autophagic effect in BV‐2 cells. Furthermore, the autophagy was activated through the AMPK/ULK1, Raf/MEK/ERK and ATG7 dependent, but independent of mTOR signaling pathway. In Aβ1‐42 induced BV‐2 cells, SMU‐A inhibits inflammasome containing NLRP3, ASC, IL‐1β and caspase1 via autophagy, which was reversed by the autophagic inhibitors such as compound C, SCH772984, hydroxychloroquine and SBI‐0206965. Additionally, SMU‐A can improve cell viability of PC12 induced injury by cell culture medium of Aβ‐induced BV‐2. Taken together, enhanced microglial autophagy is a promising new therapeutic strategy for AD, and demonstrate the autophagy inducers in SMU exerts the potential neuroprotective mechanism in suppressing neuroinflammatory responses by enhancing autophagy in microglial. Therefore, uncovering the components in SMU contributing to autophagy activation and its molecular mechanism provide new insight of PCP into novel therapies for the amelioration of AD.Support or Funding InformationThe Science and Technology Program of Luzhou” (grant numbers 2016LZXNYD‐T03 and 2017LZXNYD‐J28), “Educational Commission of Sichuan Province” (grant numbers 18ZA0528 and 18TD0051), “Science and Technology Planning Project of Sichuan Province” (grant numbers 2018JY0474 and 2018JY0237)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects and Side Effects of Cannabinoid/Opioid Combination in a Chronic Pain Model in Rats
Authors: Alsalem Mohammad , Altarifi Ahmad , Aldaoud Nour 
Published: June 2021

Chronic pain is considered a growing healthcare problem becoming a major cause of global burden. Prolonged use of the currently used analgesics such opioids is associated with adverse effects; urging the need for safer alternatives. Cannabinoids are a group of compounds structurally related to Δ9‐tetrahydrocannabinol (Δ9‐THC). Both cannabinoids and opioids produce antinociception in different chronic pain animal models. However, therapeutic doses of these drugs may be accompanied by undesirable side effects, such as abuse liability and decrease locomotion in animals. The aim of this study was to assess the outcomes of combining range of doses of opioids and cannabinoids that are sufficient to produce antinociception without producing unwanted side effects. Inflammatory pain was induced by intra‐plantar injection of Complete Freund's Adjuvant (CFA) into the left hindpaw of adult male Sprague Dawley rats. Von Frey filaments were applied to the mid‐plantar aspect of the left hind paw using the “up‐down” method to determine the CFA‐induced mechanical allodynia. Antinociceptive effect of morphine (0.32, 1 and 3.2 mg/kg; i.p), the synthetic cannabinoid CP55940 (0.032, 0.1 and 0.32 mg/kg; s.c.), their combinations, or their vehicles was evaluated 3–9 day post‐CFA administration. Intracranial self‐stimulation (ICSS) test was utilized to evaluate the abuse liability of these drugs or their combinations. Morphine produced significant antinociceptive effects at 1 and 3.2 mg/kg, but not at the lowest dose of 0.32 mg/kg with minimal changes in ICSS. CP55940 showed significant antinociceptive effects only at the highest administered dose (0.32 mg/kg), while producing depression in ICSS at 0.1 and 0.32 mg/kg. The sub‐theraputic dose of morphine (0.32 mg/kg) was co‐administered with the different doses of CP55940 (0.032, 0.1 and 0.32 mg/kg). 0.32 mg/kg morphine enhanced the antinocicpetive effects of CP55940, such that CP55940 produced antinociception at lower dose (0.1 mg/kg) compared to vehicle. However, in ICSS test, the aforementioned combinations did not change CP55940‐induced depression of ICSS. In conclusion morphine and CP55940 produce analgesic effects at lower doses if combined together with no additional risk of abuse liability side effects, which may be useful in clinical practice.Support or Funding InformationScientific Research Support Fund (MPH/1/29/2016)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Arachidonoyl‐2‐chloroethylamide alleviates inflammatory pain in a sex‐dependent manner using the formalin test
Authors: Garcia Dianise Rodriguez , Lugo‐Rodriguez Ismael , Blanton Henry , Guindon Josee 
Published: June 2021

Previous studies have shown that certain cannabinoids have analgesic effects. Specifically, activation of cannabinoid receptor (CB) 1 has been demonstrated to produce analgesia in multiple animal models. Arachidonyl‐2‐chloroethylamide (ACEA) is a synthetic agonist for CB1 receptors. The activation of CB1 with ACEA could enable chronic inflammatory pain patients to manage this discomfort. ACEA has not been extensively studied in animal models; therefore, not much is known about the dose effectiveness, development of tolerance, or sex‐specific effects.To study the analgesic effects of ACEA, we treated male and female C57BL6J mice prior to the formalin pain test. Administration of formalin (2.5% intraplantar) produces a biphasic pain response, modeling both acute and inflammatory pain. We believe that administration of ACEA at a dose of 0.5 mg per kg intraperitoneal will reduce inflammatory pain in this model. Also, we suggest that daily pretreatment with ACEA prior to the formalin test will cause desensitization to this compound; therefore, the initial analgesic effect will not be seen. To examine sex‐specific effects, we also tested and compared male and female mice. Moreover, vaginal lavage was performed daily on female mice to track the estrous cycle.Preliminary data suggests that females experience higher pain sensitivity compared with males when ACEA 0.5 mg per kg was used. Furthermore, our preliminary data shows that chronic administration in females results in estrous cycle changes. We concluded that there is a sex‐dependent difference in analgesic response to ACEA, and that it may be hormonally‐mediated.Support or Funding InformationFunded by NIDA DA044999‐01A1 (JG) and Texas Tech University Health Sciences Center School of Medicine #121035 (JG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comparison of the anti‐allodynic effects of gabapentin, morphine and N‐palmitoylethanolamide in rats with chronic constriction of the sciatic nerve
Authors: Hernández Yisel Blanco , Valdés Licet Caridad Mena , Muñoz Francisco Javier López 
Published: June 2021

Neuropathic pain (NP) is a chronic disorder with a complex and multifactorial etiology. The NP prevalence constitute a significant health problem worldwide. Among the first choice drugs used for NP treatment is gabapentin (GBP), an antiepileptic drug and morphine (MOR), a prototype of analgesic opioid drug. Moreover, it has recently described the antinociceptive effects of N‐palmitoylethanolamide (PEA) on inflammatory pain.ObjectiveTo evaluate and compare the anti‐allodynic effects of GBP, MOR and PEA in rats with chronic constriction of the sciatic nerve (CCI model).MethodsThe anti‐allodynic effects of GBP (3.16–177.83 mg/Kg, p.o.), MOR (0.010–3.16 mg/Kg, s.c.) and PEA (3.16–10.00 mg/Kg, p.o.) were determined after single‐doses, using could allodynia test in the CCI model. Evaluations were done until 10 days post‐surgery at 30, 60, 90, 120 and 180 minutes after drugs administration.ResultIt was found that GBP, MOR and PEA showed anti‐allodynic effects in rats with NP induced by CCI. PEA achieved the same anti‐allodynic efficacy as the control group (GBP) and similar to the maximum efficacy achieved by MOR (p>0.05). The analysis of pharmacological potency demonstrated that: MOR (ED50 = 0.047 mg/Kg) was 28 time more potent than PEA (ED50 (1.319 mg/Kg), but PEA was 78 time more potent than GBP (ED50 = 103.3 mg/Kg).ConclusionsThese results demonstrate that PEA have anti‐allodynic effect similar to MOR and GBP, and also that PEA is more potent than GBP in rats with NP induced by CCI.Support or Funding InformationDepartment of Pharmacobiology, Cinvestav‐Unidad Coapa, C.P. 14330, Tlálpan, Mexico City, Mexico.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differences in Depressive‐ and Anxiety‐like effects in S426A/S430A Mutant and Wild‐type Mice Following the Induction of Neuropathic Pain
Authors: Sepulveda Diana E , Oleksyuk Veronika , Nolan Bradley J , Morgan Daniel J , Henderson‐Redmond Angela N 
Published: June 2021

Clinically, chronic pain has been associated with increases in anxiety‐ and depressive‐like symptoms, concomitant with the severity and duration of pain. Pursuant to the on‐going opioid crisis, novel therapeutic approaches, including the use of cannabinoids, have been investigated for the management of chronic pain. We have previously demonstrated that mice expressing a desensitization form of the cannabinoid type‐1 (CB1) receptor (S426A/S430A) show delayed tolerance and heightened sensitivity to the anti‐nociceptive effects of Δ9‐tetrahydrocannabinol (Δ9‐THC). In addition to analgesia, cannabinoids have been implicated in mediating affect in select mood disorders. Therefore, the purpose of the present study was to examine whether the induction of chronic neuropathic pain would alter anxiety and/or depressive‐like phenotypes in either wild‐type and/or S426A/S430A mutant mice, and whether the severity of these symptoms correlated with either basal allodynia or Δ9‐THC‐induced anti‐allodynic responses. Male and female wild‐type and S426A/S430A mice were assessed for alterations in locomotor behavior, anxiety‐like (elevated plus maze; open field) and depressive‐like (forced swim test) behaviors before and after the induction of cisplatin‐evoked neuropathic pain. Mice were also assessed to see whether basal pain levels correlated with either anxiety‐ and/or depressive‐like behaviors, and whether increased anxiety‐ and/or depressive‐like symptoms correlated with the degree of anti‐allodynia produced following pretreatment with Δ9‐THC. All mice showed evidence of neuropathic pain following repeated cisplatin‐treatment. Interestingly, the S426A/S430A mutation caused female (but not male) mice to exhibit reduced anxiety‐like behavior prior to the induction of cisplatin pain but caused them to be more susceptible to anxiety and depressive‐like symptoms once they exhibited cisplatin‐evoked pain. Pretreatment with Δ9‐THC was also able to completely reverse allodynia in male and female mutant, but not wild‐type, mice. Taken together, these results highlight the importance of understanding the role that sex may have in the potential clinical use of cannabinoids to modulate both affective and sensory aspects of chronic pain.Support or Funding InformationPenn State University College of Medicine Department of Anesthesiology & Perioperative MedicineThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.