bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antioxidant and anti‐apoptotic effect of Gallic acid on doxorubicin‐induced testicular and epididymal toxicity
Authors: Oyeyemi Matthew Olugbenga , Moyinoluwa Olusoji Adetokunbo , Asenuga Ebunoluwa Racheal , Omobowale Temidayo Olutayo , Ajayi Olusola , Oyagbemi Ademola Adetokunbo 
Published: June 2021

The effect of Gallic acid (GA) on doxorubicin (DOX) induced testicular and epididymal toxicity was investigated in experimental rat model. The rats were randomly divided into six groups of 10 animals per group. Rats in group A received clean tap water ad libitum. Rats in group B were administered DOX intraperitoneally at 15 mg/kg on the eighth day of the experiment. Animals in groups C and D received 60 and 120 mg/kg GA orally for 7 days with 15 mg/kg DOX on the eighth day. Rats in groups E and F received 60 and 120 mg/kg GA alone orally for 7 days. The animals were sacrificed 24 hr after the last administration. DOX administration led to a significant (p < 0.05) increase in hydrogen peroxide and malondialdehyde levels with significant reduction in antioxidant enzymes and reduced glutathione levels. DOX administration also led to a significant increase in total sperm abnormalities and prolactin together with a significant decrease in testosterone levels. Immunohistochemistry revealed higher expressions of caspase 3 in the testicular tissues of rats that received DOX alone. Together, pre‐treatment with GA attenuated markers of oxidative stress, reversed sperm abnormality and ameliorated the observed aberration in plasma testosterone and prolactin levels.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cytoprotective Effect of two Flavanoids ‐ Catechin and Epicatechin, Against Oxidative Stress Induced by Cumene Hydroperoxide, in MCF‐7 Cells
Authors: Alghamdi Raed , Kerr Stephen G. 
Published: June 2021

Reactive Oxygen Species (ROS) are generated during normal cellular metabolic activity, especially in the electron transport chain and in biological redox reactions. Cumene Hydroperoxide, (CHP) a potent source of ROS, is commonly used in the chemical manufacture of phenols, acetone and polymers and can result in inadvertent exposure to individuals working in this chemical industry. CHP is known to initiate lipid peroxidation and increase ROS levels in membranes, which can lead to oxidative stress and cell death. The aim of the study was to investigate the cytoprotective activity of two flavonoids, catechin and epicatechin against the oxidative stress induced by CHP. The method involved comparing the % cell viability between cells treated with CHP for 4h alone and cells pretreated with catechin or epicatechin for 24 or 48 hr prior to treatment with CHP. MTS cell proliferation assays (Abcam) was used to determine cell viability after exposure. Approximately 1×104 cells/100μL/well of MCF‐7 cells were seeded in a 96‐well plates. After 24 hours, the cells were treated with CHP (50–350 μM) for 2h, 4h or 24h to determine viability. Cells were also treated with catechin (100–500μM), epicatechin (100–500μM), DMSO or control for 24 or 48 hr. Additionally, cells were pretreated with catechin (100–500μM) or epicatechin (100–500μM) and then exposed to 100μM CHP for 4 hours. % cell viability was then determined by the MTS assay system. The results of individual treatments indicated that there was a concentration dependent cell toxicity of CHP at concentrations > 50μM CHP compared to control when cells were exposed for 4 hr to CHP (IC50 = 100 μM). All concentrations of catechin and epicatechin showed no significant loss of cell viability as compared to the control after both 24 and 48h hr exposure. In the pre‐treatment studies, 100μM of CHP showed 50% decrease in cell viability after 4h of treatment, however when the cells were pretreated for 24 hr with catechin (400–500 μM) or epicatechin (400–500 μM) there was protection of 10–20% from the cytotoxic effects of CHP. Concentrations lower than 400 μM of catechin and epicatechin did not show protection. At 48h of pretreatment with catechin and epicatechin, enhanced protection (20 – 30 %), compared to the 24 hr pre‐treatment, was observed with 300–500 μM concentrations of catechin and epicatechin. The results clearly demonstrate that catechin and epicatechin at concentrations of 300 – 500 μM are cytoprotective to MCF‐7 cells against oxidative stress induced by exposure to 100 μM CHP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identifying Diazepam Induced Alterations in GABA Type A Receptor Synaptic Plasticity
Authors: Lorenz‐Guertin Joshua , Das Sabyasachi , Pardo Sammy , Molleur Dana , Weintraub Susan , Jacob Tija C. 
Published: June 2021

The mechanisms underlying tolerance to the benzodiazepine (BZD) drug class are poorly understood. BZDs potentiate the actions of gamma‐aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABAAR). Our work uses the classical BZD, diazepam (DZP), for in‐vitro and in‐vivo experiments combined with novel live‐imaging and biochemical methods to identify BZD‐induced changes in GABAAR signaling. Previous findings from our lab and others have implicated trafficking mechanisms in the loss of BZD potentiation associated with tolerance. Microscopy studies of endogenous GABAARs in rat cortical neurons indicate 24 hr exposure of 1μM DZP causes a reduction in extrasynaptic γ2 levels and modification of the inhibitory synaptic scaffolding protein gephyrin. Immunoprecipitation experiments uncover enhanced ubiquitination of the γ2 subunit and reduced total levels in‐vitro following DZP. Biochemical studies of mice injected with 10 mg/kg DZP vs vehicle also show a significant decrease in γ2 subunit and total gephyrin cortical levels 12 hr post DZP injection. Live‐imaging studies using a novel GABAAR γ2 subunit encoding a N terminal fluorogen‐activating peptide (FAP) and pH‐sensitive green fluorescent protein (γ2pHFAP) identified elevated lysosomal targeting of γ2 following DZP. Furthermore, RFP‐gephyrin and γ2‐GABAARs exhibit enhanced synaptic diffusion rates after 24 h DZP as measured by fluorescence recovery after photobleaching experiments. Overall, our work suggests DZP treatment decreases γ2 GABAAR inhibitory function by reducing synaptic dwell time and surface levels after one day of exposure, which may contribute to the formation of DZP tolerance.Support or Funding InformationThis work was generously funded by T32GM008424, the Whitehall Foundation, the William C. deGroat neuropharmacology departmental fellowship and Pharmacology and Chemical Biology Startup Funds. The FAP, MG dyes, and critical guidance was provided by Ming Zhang, Brigitte Schmidt, and the Waggoner Lab at Carnegie Melon University. S. Das performed animal injections and tissue collection.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Organ Distribution and Clearance of (3,4)‐Methylenedioxypyrovalerone (MDPV) Enantiomers in Female and Male Rats after Intravenous Administration of Racemic MDPV
Authors: Hambuchen Michael D. , Hendrickson Howard P. , Gunnell Melinda G. , McClenahan Samantha J. , Owens S Michael 
Published: June 2021

The objective of these studies was to characterize the organ distribution and clearance of (S)‐ and (R)‐MDPV in female and male Sprague Dawley rats after administration of (R,S)‐MDPV, hypothesizing that there would be enantiomer and sex dependent differences in organs most relevant to MDPV pharmacology such as the brain, heart, and liver. After administration of an intravenous 3 mg/kg dose of (R,S)‐MDPV, male and female rats (n=4–5/time point of collection/sex) were euthanized, and blood, brain, kidney, liver, heart, and spleen were rapidly collected at 5, 20, 60, 90, and 120 min after dosing. (S)‐ and (R)‐MDPV enantiomers were quantified in serum and homogenized organs by a chiral liquid chromatography tandem mass spectrometry technique. While substantial concentrations of both enantiomers accumulated in kidney tissue of both sexes, unchanged renal clearance was only a minor contributor to MDPV total body clearance (0.6 – 1.5%). These data indicated that MDPV metabolic clearance was the major route of elimination of unchanged MDPV. In the liver, concentrations of both enantiomers were substantially lower than in the kidney, and, interestingly, there were significantly (p<0.05) lower liver concentrations of (S)‐ than (R)‐MDPV in both sexes. These data indicated that the liver had a higher intrinsic metabolic clearance for the (S)‐enantiomer than the (R)‐enantiomer. This may also explain why the blood concentrations of (R)‐MDPV were consistently higher than the concentrations of (S)‐MDPV. There was a time‐dependent increase in the ratio of the more potent (S)‐ compared to (R)‐enantiomer in the brain and heart in both sexes. Also, measures of brain concentrations of both enantiomers were significantly (p<0.05) elevated in male compared to female rats. In conclusion, renal clearance of unchanged MDPV was insubstantial in both sexes. Clearance of MDPV was predominantly metabolic with the liver preferentially eliminating (S)‐MDPV. Additionally, the brain and heart S/R enantiomeric ratio showed significant (p<0.05) increases over time in male and female rats. This may contribute to (S)‐MDPV having greater potency than (R)‐MDPV at sites of action in these two organs.Support or Funding InformationFunded by NIDA grants DA039195 and T32 GM106999This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Impact of Sex and Exercise on Methamphetamine Preference in a Rat Animal Model
Authors: Purpura Mari , Kippin Tod E. , Williams Serina , Barkas Christina , Adams Julia 
Published: June 2021

Methamphetamine (METH) abuse remains an extremely serious problem in the United States. METH has a long duration of action, and therefore leads to prolonged stimulant effects. Currently, there is limited information on the individual differences in vulnerability to substance use disorder (SUD) and how subject factors may impact the selection of METH over a competing reinforcer. Explore the factors contributing to addiction vulnerability for METH in an animal model by comparing sex, dose and ITI. Expand our understanding of the relation between exercise and addiction. If the reward for exercise and drug taking have overlapping circuitry, then engaging in exercise may reduce the need for drugs. To explore factors contributing to addiction vulnerability for METH in an animal model, we compared sex, dose (0.05 and 0.1 mg/kg/inf IV), short (20 s) or long (10 min) inter‐trial intervals (ITI) and the effects of exercise on the behavioral allocation of effort on drug taking. Rats were allowed voluntary exercise in Whamann wheels (6 hr/day, 4 weeks) followed by assessment of choice between METH (1 mg/kg/inf IV, FI20s) or food (2□3×45 mg, FI20s) reinforcement in standard operant chambers. There was a significant interaction between sex and dose (F,145)=5.765, p=0.021. ITI of 20 s and dose of 0.1 mg/kg/inf was the most preferred combination and females exhibited higher and more plastic (i.e. dose dependent) selection between METH over a competing reinforcer. There was a negative relationship between running wheel rotations/hour and preference for METH, and a significant effect of treatment (exercise versus control) amongst the METH preferring rats F(1,11)=5.133, p=0.045. Engagement of voluntary exercise may decrease vulnerability and increase resilience to the development of a SUD amongst a subpopulation that is initially METH preferring. Generally, the results of this study are consistent with the growing body of clinical and preclinical evidence demonstrating that females exhibit higher addiction vulnerability for stimulant drugs of abuse.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neurochemical and Cardiovascular Effects of β‐Methylphenethylamine (BMPEA) Analogs Found in Dietary Supplements
Authors: Baumann Michael H. , Thorndike Eric B. , Rice Kenner C. , Schindler Charles W. 
Published: June 2021

Dietary supplements often contain additives not listed on the label. β‐Methylphenethylamine (BMPEA, 2‐phenylpropan‐1‐amine), a structural isomer of the stimulant drug amphetamine, is one such additive. The objective of this study was to determine the neurochemical and cardiovascular effects of BMPEA and its analogs, N‐methyl‐2‐phenylpropan‐1‐amine (MPPA) and N,N‐dimethyl‐2‐phenylpropan‐1‐amine (DMPPA). Synaptosomes were prepared from rat caudate tissue for dopamine transporter (DAT) assays or from whole rat brain minus caudate and cerebellum for norepinephrine transporter (NET) assays. Five male Sprague‐Dawley rats received surgically‐implanted telemetry transmitters for the measurement of blood pressure (BP), heart rate (HR) and locomotor activity. Rats were placed into acoustical cubicles for 3 h each weekday, and drug or vehicle was administered on Tuesdays and Fridays. As expected, amphetamine was a potent substrate‐type releasing agent at DAT (EC50=5 nM) and NET (EC50=8 nM). Like amphetamine, BMPEA was a releaser at DAT (EC50=627 nM) and NET (EC50=125 nM), and MPPA had similar effects. DMPPA was a weak substrate only at NET (EC50=1337 nM). In general, the transmitter releasing actions of BMPEA analogs were more potent at NET than DAT. Amphetamine (0.3–3.0 mg/kg, sc) produced significant dose‐related increases in BP, HR and activity (all F[4,34] > 8.9, p < 0.05). By contrast, BMPEA, MPPA and DMPPA (3.0 and 30 mg/kg, sc) produced significant increases in BP (all F[3,27] > 4.1, p < 0.05) but failed to clearly affect HR or activity. The hypertensive effect of BMPEA was reversed by pretreatment with the α‐adrenergic antagonist prazosin. Our results show that BMPEA and its analogs are biologically active. Although these compounds are unlikely to be abused due to weak effects at DAT, they could produce adverse cardiovascular complications due to prominent transmitter releasing activity at NET.Support or Funding InformationSupported by IRP, NIDA, NIH, DHHS.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dopaminergic Perturbations from Food Restriction and Exercise are Sex‐Dependently Amplified During Adolescence
Authors: Gilman T Lee , Owens W Anthony , George Christina M. , Metzel Lauren , Daws Lynette C. 
Published: June 2021

Eating disorders, which are 2.5‐fold more prevalent in females than males, typically emerge during adolescence. Afflicting at least 3 percent of teenagers, eating disorders such as anorexia nervosa, bulimia nervosa, and binge eating disorder entail severe health consequences in addition to their psychological toll. Yet no effective treatments for eating disorders exist. An established regulator of both eating behaviors and physical activity, the dopaminergic system undergoes a sensitive maturation period during adolescence. However, studies into the role of the dopaminergic system in ontogeny of eating disorders are lacking, as are investigations into dopaminergic system maturation in adolescent females. Here we measured function of the dopamine transporter (DAT), a critical regulator of dopaminergic signaling, using both in vivo high‐speed chronoamperometry and locomotor assays of acute cocaine response. Employing an activity‐based anorexia paradigm for 4–5 days, we investigated how food restriction, free exercise on a running wheel, or the combination thereof impacted DAT function in adult (postnatal day 90) and adolescent (postnatal day 30) Sprague‐Dawley rats of both sexes. Food restriction alone or with exercise in adolescent rats of both sexes produced leftward shifts in the dose‐response to the locomotor‐promoting effects of cocaine, though the maximal response to cocaine was blunted in females within these two groups. In adults, only food restricted females exhibited a significant increase in maximal cocaine‐induced locomotor response. Clearance of dopamine in dorsal striatum was not significantly altered by food restriction and/or exercise in adults. In contrast, food restriction plus exercise significantly attenuated dopamine clearance in adolescent males, and food restriction alone or combined with exercise elicited pronounced dopamine clearance reductions in adolescent females. Together, these findings suggest that adolescent plasticity of the dopaminergic system confers – particularly in females – vulnerability to eating disorders and persistence of associated unhealthy behaviors (e.g., compulsive exercise). Therefore, drugs that enhance dopamine uptake or otherwise reduce dopamine signaling duration may prove efficacious in the treatment of emerging adolescent eating disorders. Ongoing experiments are evaluating striatal DAT expression in these animals, and future experiments will focus on optimizing longer term food restriction and exercise conditions in adolescents to facilitate investigation of pharmacologic interventions.Support or Funding InformationThis research was supported by R21 DA038504 to LCD. TLG is supported by T32 DA031115 to Charles P. France.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Behavioral Effects of α2/α3 Subtype‐Selective GABAA Receptor Positive Allosteric Modulators
Authors: Lewter Lakeisha , Cook James M. , Li Jun‐Xu 
Published: June 2021

Millions of individuals suffer from chronic pain. Opioids are effective for treating chronic pain but their use is limited due to undesirable side‐effects. Previous studies have shown that different subunits of the GABAA receptor are associated with different actions of the benzodiazepine site. While α2/α3 subunit‐containing GABAA receptors mediate antinociceptive effects, α1 subunit‐containing GABAA receptors mediate sedative and abuse‐related effects. This study sought to examine the behavioral effects of two α2/α3‐subtype selective PAMs: KRM‐II‐81 and NS16085. In a rat model of inflammatory pain (complete Freund's adjuvant) and a rat model of neuropathic pain (chronic constriction injury), both PAMs and the classical benzodiazepine midazolam attenuated mechanical hyperalgesia (as measured by von Frey test). In the procedure of food‐maintained operant responding, KRM‐II‐81 and NS16085 did not significantly decrease the response rate at doses that produced maximal antinociception. Contrastingly, midazolam significantly reduced the response rate at doses that attenuated mechanical hyperalgesia. In a horizontal wire test aimed to measure muscle relaxation, within the dose range that produced antinociception, only midazolam dose‐dependently increased the percentage of rats unable to grasp the wire, indicating muscle‐relaxant activity. These behavioral effects can be attenuated by benzodiazepine receptor antagonist flumazenil, confirming that the behavioral effects of these subtype‐selective GABAA PAMs are mediated through the benzodiazepine site of GABAA receptors. Taken together, while midazolam produced antinociceptive, rate‐suppressing, and muscle‐relaxant activity at similar doses, both subtype‐selective GABAA receptor PAMs selectively produced antinocicpetive effects. Collectively, these data support the notion of α2/α3‐subtype selective GABAA PAMs as novel analgesics.Support or Funding InformationR01DA034806This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Neuropeptide Receptor System, BigLEN‐GPR171, Interacts with the Opioid System to Relieve Pain
Authors: Afrose Leela , Gomes Ivone , Devi Lakshmi A. , Bobeck Erin N. 
Published: June 2021

ProSAAS derived peptides, such as BigLEN, are abundantly expressed throughout the brain. We recently identified BigLEN as the endogenous peptide for the orphan receptor GPR171. Immunohistochemical analysis shows that both BigLEN and GPR171 are highly expressed in areas of the brain involved in pain modulation, including the periaqueductal gray (PAG). In addition, we find that GPR171 is co‐localized with mu opioid receptors (MOPr) in the ventrolateral PAG. Also, using immunohistochemistry we have identified that GPR171 is expressed in a portion of vGLut2 and GAD67 positive neurons. This brain region is especially known to contribute to opioid antinociception and tolerance. Given the expression pattern of GPR171, we hypothesized that GPR171 contributes to antinociception and tolerance. To test this, mice were injected with a GPR171 antagonist (MS21570; 5 mg/kg, i.p.) followed by the tail flick pain test which produced an increase in antinociception compared to controls. However, this compound is not as efficacious as morphine and pretreatment with MS21570 10 min prior to morphine (10 mg/kg, s.c.) did not alter morphine‐induced antinociception. To assess the role of GPR171 in morphine tolerance, mice were injected with morphine twice daily for 5 days. A subset of mice were pretreated with MS21570 10 min prior to each morphine injection. Those mice pretreated with MS21570 showed a decrease in the development of morphine tolerance. To understand how these systems may be working together, GPR171 was knocked down in Neuro2A cells which led to a decrease in MOPr‐mediated GTPγS signaling by DAMGO, but had no effect on GTPγS signaling by the delta opioid receptor agonist, deltorphin. This data suggests that the MOPr agonist, DAMGO, requires GPR171 expression in order to signal despite not directly binding to GPR171. Studies investigating GPR171 expression and signaling changes within the PAG following chronic morphine are ongoing. Taken together, this data shows that GPR171 and MOPr interact with one another and GPR171 antagonist may be a novel target to treat pain or opioid tolerance.Support or Funding InformationSupported by NIH grants, DA019521 and NS026880 (to LAD) and NIDA postdoctoral training grant DA007135 and a Young Investigator Grant from the Brain and Behavior Research Foundation (to ENB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.