bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of Mitofusin2 in neurons slows down skeletal muscles atrophy in ALS disease and aging model
Authors: Wang Luwen , Gao Ju , Wang Xinglong 
Published: June 2021

Skeletal muscles undergo atrophy in response to diseases and aging. Mitochondria, the source of cellular energy, were found to be fragmented in experimental models of ALS disease and aging. However, whether and how mitochondrial fragmentation plays a role in the progression of disease and aging is not clear. Mitofusin2 (Mfn2) is a key regulator of mitochondrial fusion which is crucial for the maintenance of mitochondrial morphology. To test whether Mfn2 reduction in motor neurons contributed to the disease progression in SOD1G93A mice or aged mice, we generated transgenic mice overexpressing Mfn2 specifically in neurons under the control of the Thy1.2 promoter (TMFN mice). Mfn2 overexpression was confirmed in spinal cords but not skeletal muscles. By crossing Mfn2 overexpressed mice with SOD1G93A mice, we obtained double transgenic Mfn2/SOD1G93A mice. Interestingly, mitochondrial fragmentation was abolished in motor neurons of Mfn2/SOD1G93A mice even in the disease endstage. Strikingly, characteristic neuromuscular junction (NMJ) denervation, collapse, and dysfunction in SOD1G93A mice were also greatly alleviated in Mfn2/SOD1G93A mice. The dramatic protective effect of neuronal Mfn2 in SOD1G93A mice was further indicated by the greatly delayed symptom onset of more than 60 days and the complete prevention of behavioral deficits at 120 days old, a very late stage immediately before endstage onset.A similar protective effect was observed in aged mice. The Mfn2 neuronal overexpression mice suffered less neuromuscular synaptic dysfunction and skeletal muscle atrophy than their non‐transgenic litter mates even at 22 months old, which in human years is equivalent to the 70s. Taken together, our study provides evidence suggesting that Mfn2 deficiency induced mitochondrial fragmentation in motor neurons is likely an important mechanism leading to NMJ dysfunction and skeletal muscle atrophy in ALS and aging, and that Mfn2 could be a common therapeutic target for skeletal muscle atrophy.Support or Funding InformationThis study is supported by grants from the US NIH (1R01NS097679 and 1R01NS089604), US Alzheimer's Association (AARG‐17‐499682), and US Association for Frontotemporal Degeneration and Alzheimer's Drug Discovery Foundation (20161206).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Pharmacological Characterization of Kappa Opioid Receptor Agonists
Authors: Kaska Sophia , Kornberger Lindsay , Biggerstaff Andrew , Kivell Bronwyn , Prisinzano Thomas 
Published: June 2021

Agonists of the kappa opioid receptor (KOR) demonstrate promise for treating pain without the typical side effects of mu opioid receptor agonists, such as respiratory depression and tolerance. Unfortunately, KOR agonists have their own side effects such as sedation and dysphoria, which necessitates further development of new KOR agonists that will maintain analgesic effects while eliminating these negative side effects. Through structure‐activity relationship studies, our laboratory has identified a series of potent and selective KOR agonists that demonstrate functional selectivity for the G‐protein pathway, increasing the propensity to display analgesic effects with fewer side effects that are mediated through beta‐arrestin. Furthermore, in vivo evaluation of the analgesic effects of these compounds demonstrated an increase in potency, compared to U50,488, consistent with our in vitro data. To further demonstrate the analgesic effects of our compounds, a time course experiment was performed using the hot water tail flick assay. Over this time course, these analogs at lower doses demonstrated the same efficacy compared to U50,488, indicating an increase in analgesic effect of these compounds. Together, these data demonstrate that our series of KOR agonists have improved in vitro and in vivo activity compared to U50,488 and can potentially be used for treating pain.Support or Funding InformationThis work was supported by NIH R01 DA018151 and the Health Research Council of New Zealand.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Buprenorphine C7‐Esters with Improved Nociceptin Receptor Agonist Potency as Analgesics
Authors: Olson Keith Mathew , Cami‐Kobeci Gerta , Husbands Stephen M. , Traynor John R. 
Published: June 2021

There is an urgent need for analgesics with reduced abuse liability, withdrawal, respiratory depression and constipation to treat chronic pain patients. While clinical opiates produce analgesia and associated side effects through Mu Opioid Receptor (MOR) agonist activity, preclinical evidence indicates activity at the Kappa‐ (KOR), Delta‐ (DOR), and Nociception Receptors (NOP) subtypes can minimize side effects. Compounds displaying NOP agonist and weak MOR partial agonist activity produce antinociception with minimal abuse liability in primates and therefore are desirable therapeutic target. In the present study we evaluated buprenorphine analogues with C7 ester substituents for opioid receptor affinity by competition binding assay and for function using the [35S]‐GTPgS assay at MOR, NOP, DOR and KOR. Compounds showed a nearly 1000‐fold range in binding and [35S]‐GTPgS activity at NOP, ranging from low nanomolar to micromolar. One compound, containing a phenyl ester at C7, and lacking a keto group at C6, showed the highest potency NOP activity (EC50= 0.97 +/− 0.22 nM, EMAX= 47% +/− 11) with weak partial agonist potency at MOR (EC50= 3.9 +/− 1.3 nM, EMAX= 23% +/− 7). Since this compound has less MOR agonist efficacy than buprenorphine, it would be predicted to have minimal abuse liability. The series also showed a synergistic relationship in NOP activity between the C7 functional group and the C6 oxidation state. For example, the presence of a keto group at C6 decreased NOP potency significantly (EC50= 164 +/− 51 nM, EMAX= 47% +/− 9). This pattern was observed with numerous C7 functional groups. All compounds in the series were putative antagonists at DOR and KOR as they bound with high affinity but did stimulate significant activity in the [35S]‐GTPgS assay. This series of compounds provides different degrees of partial agonism at MOR and NOP and should help to determine the minimal MOR activity necessary for effective antinociception while minimizing potential abuse liability.Support or Funding InformationSupported by R01 DA07315 and 035316.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 of the mGluR2/3 agonist LY379268, alone and in combination with monoamineenhancing drugs, on cocaine self‐administration in rhesus monkeys
Authors: Czoty Paul W , Coller Michael , Odom Jill , Landavazo Antonio , Blough Bruce E , Nader Michael A 
Published: June 2021

Cocaine addiction persists as a major public health problem but still lacks any FDA‐approved pharmacotherapies. Wake Forest's Center for the Neurobiology of Drug Abuse Treatment (CNAT) has demonstrated the effectiveness of ‘agonist medications’ such as the monoamine releaser phenmetrazine (PM) and its pro‐drug phendimetrazine (PDM) to decrease cocaine use in animal models. CNAT investigators have hypothesized that combination of a dopamine‐enhancing drug like PM/PDM with a drug with a different pharmacological and/or behavioral mechanism may display enhanced effectiveness and represent a promising pharmacotherapeutic approach to treating cocaine use disorder. The present studies characterized the effects of the mGluR2/3 receptor agonist LY379268, alone and in combination with daily PDM or the dopamine transporter inhibitor methylphenidate (MPD) on cocaine reinforcement in rhesus monkeys. In one experiment (n=4), a multiple schedule was used in which food reinforcers were available in the first component under a fixed‐ratio schedule of reinforcement and cocaine self‐administration was studied under a progressive‐ratio schedule. A second study (n=4) used a food‐cocaine choice procedure in which a complete cocaine dose‐effect curve was generated each day. Effects of acute and chronic LY379268 were studied. Under the multiple schedule, acute LY379268 decreased food‐but not cocaine‐maintained responding; when administered chronically (as an i.v. injection) during chronic oral PDM treatment, a drug combination that persistently decreased cocaine self‐administration was found in only one of four subjects. Under the choice procedure, LY379268 increased the reinforcing strength of cocaine relative to food. After 5 days of treatment, tolerance developed to this effect in a dose‐related manner but at no point were decreases in cocaine choice observed. Finally, when chronic LY379268 was administered in combination with chronic oral PDM or chronic MPD (via subcutaneous osmotic pump), dose combinations were observed that modestly decreased cocaine choice in two of four monkeys. Although some results were positive, taken together these studies, which used highly translational nonhuman primate models of cocaine use disorder, do not support the effectiveness of LY 279638 alone or in combination with agonist medications.Support or Funding InformationP50 DA06634This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Varying Effects of the G‐Protein Coupled Estrogen Receptor During Development in Embryonic Rat Hippocampal and Cortical Neurons
Authors: Pemberton Kyle , Xu Fenglian 
Published: June 2021

Estrogen has been known to play a role in enhancing brain development for over half a century. Most studies of estrogen's effect on the nervous system have focused on the traditional estrogen receptors Estrogen Receptor‐α (ERα) and Estrogen Receptor‐β (ERβ). The recent discovery of the G‐Protein Coupled Estrogen Receptor (GPER) suggests knowledge of estrogen's effects may be incomplete. While evidence has suggested the roles GPER plays in the nervous system include neuroprotection, neuronal recovery from stroke and degeneration, neuron proliferation, as well as many others. A caveat is that most studies have looked only at the effect in mature neurons and not the effect GPER has during early neuronal development. Here we sought to study the role of GPER activity in neurite outgrowth and synapse formation during early development.Embryonic day 18 rat cortical and hippocampal neurons were cultured in estrogen‐ and phenol red‐ free medium in the presence of a nonselective ER agonist (E2), a selective GPER agonist (G‐1), and a selective GPER antagonist (G‐15). Neurite growth was measured at 20, 48, 72, and 96 hours in culture using the ImageJ plugin NeuronJ. Synapses were visualized at 7 and 14 days in culture by using immunofluorescence of the pre‐ and post‐synaptic markers, synaptophysin and PSD‐95, respectively. Synapse formation was measured by measuring the overlap between these markers in ImageJ. Our data revealed activation of GPER promoted neurite growth in hippocampal neurons, but not in cortical neurons, but blocking the receptor inhibited neurite growth in cortical neurons. In addition, low levels of G1 (1μM) inhibited neurite outgrowth in cortical neurons. Cortical neurons showed no significant difference in synapse formation, while in hippocampal neurons the effect varied based on time period and dosage. This provides the first evidence that GPER activation may play different roles in brain regions, as well as having specific dosage based effects in specific regions. Future experiments will investigate the molecular and cellular mechanisms underlying the pharmacological differences in GPER effects between developing cortical and hippocampal neurons.Support or Funding InformationThis project was supported by the Saint Louis University Start‐up Fund for Dr. Xu lab and the Sigma XI Grant‐In‐Aid of Research awarded to Mr. Kyle Pemberton.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dimethyl fumarate alleviates the nitroglycerin (NTG)‐induced migraine in mice
Authors: Esposito Emanuela , Casili Giovanna , Lanza Marika , Filippone Alessia , Campolo Michela , Paterniti Irene , Cuzzocrea Salvatore 
Published: June 2021

Oxidative stress and inflammatory pathways are involved in nitroglycerin (NTG)‐induced migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the Fumaric acid esters (FAEs), dimethyl fumarate (DMF), nuclear factor E2‐related factor 2/antioxidant response element (Nrf‐2/ARE) pathway‐mediated, in regulating the hypersensitivity in a mouse model of NTG‐induced migraine. Mice were orally administered with DMF at the doses of 10, 30 and 100 mg/kg, 5 minutes after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brainand behavioral tests after 4 h by NTG‐migraine induction. The expression of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX‐2), Nrf‐2, manganese superoxide dismutase (Mn‐SOD) and heme‐oxygenase‐1 (HO‐1) were detected by Western blot. Tail flick, hot plate, formalin and photophobia tests were used to evaluate neuropathic pain and migraine‐related light sensitivity. DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF‐κB and Nrf‐2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache‐associated neuropathic pain was significantly reduced. These results provide the evidence that DMF has a modulating effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.Support or Funding InformationNo fundingThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Role of Integrin β3 in Nucleus Accumbens Function
Authors: Jameson Alexis , Carneiro Ana , Grueter Brad 
Published: June 2021

Stress disorders, depression, anxiety, and substance use disorder, are regulated by serotonin (5HT). The dorsal raphe nucleus (DRN), the major site for neuronal 5HT synthesis, sends projections to the nucleus accumbens (NAc). NAc glutamatergic synapse adaptations are consistent with changes in mood and reward, key components of stress disorders. A subpopulation of DRN projection neurons express the β3 subunit of the integrin αvβ3 receptor. The integrin αvβ3 receptor regulates extracellular 5HT concentration by modulation of 5HT transporters. Previous work has implicated this cell adhesion receptor in modulating stress, as mice lacking the β3 subunit have increased vulnerability to chronic stress. However, how NAc function is regulated by the DRN β3 subunit and contributes to maladaptive reward behaviors as seen in stress disorders is unknown.Because the β3 subunit of the integrin avβ3 receptor is only expressed in a subpopulation of 5HT neurons, this suggests that it confers a specific function to this neuronal population. Using a mouse line with selective deletion of the β3 subunit within 5HT neurons, we are able to characterize its role in 5HT synaptic transmission. Using acute brain slice whole‐cell patch‐clamp electrophysiology, we characterize how the β3 subunit of 5HT inputs contribute to glutamatergic NAc synaptic transmission. Our data suggests that selective deletion of the β3 subunit in 5HT neurons blunts excitatory synaptic strength in the NAc. This suggests that the β3 subunit in 5HT neurons modulates excitatory input to the NAc, which may relate to stress response.Support or Funding InformationNIH T32 5T32MH064913‐15This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Involvement of GLT‐1 in The Drug Seeking Like Effects of Pregabalin
Authors: Althobaiti Yusuf , Nasr Abdulrahman , Alzahrani Omar , Almalki Hussam 
Published: June 2021

Pregabalin is a GABA analogue that can bind with high affinity to voltage‐gated calcium channel to minimize excitatory neurotransmitters release. However, several case reports in Middle East and other parts of the world raised the concern of its abuse potential. We have shown in our previous studies that higher doses of pregabalin can cause drug seeking like effect in conditioned place preference (CPP) mouse model. In this study, we tested the involvement of glutamate transporter 1 (GLT‐1), which has a significant role in glutamate homeostasis and in mediating the rewarding and drug seeking effects of several drugs of abuse. Male BALB/c mice were randomly separated into four groups; the control group (C‐C) received saline in home cages and during the conditioning training. The second group (CEF‐C) received ceftriaxone (CEF) in a dose that was consistently shown to upregulate GLT‐1, (200 mg/kg, i.p.), in home cages and received saline during conditioning training. The third group (C‐Preg) received saline in home cages and were administered pregabalin in a dose that previously shown to induce CPP (60 mg/kg) during conditioning training. The last group (CEF‐Preg) received CEF in home cages and injections of pregabalin during the conditioning training. Consistent with our previous studies, the time spent in drug‐paired chamber as compared to the vehicle‐paired chamber was significantly increased in C‐Preg group. Importantly, CEF treatment for eight days blocked pregabalin induced CPP. These results showed for the first time the possible involvement of GLT‐1 in mediating the rewarding effects of pregablin in animal model of drug addiction.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulation of Mood by Dopamine D1 Receptors on Cerebral Cortical Interneurons
Authors: Stanwood Gregg , Jin Yuanhu , Graham Devon 
Published: June 2021

Depression is a multifactorial brain disorder caused by a variety of alterations in neural structure and function. We have used the Cre/loxP system to selectively delete dopamine D1 receptors from GABAergic neurons from the Nkx2.1 lineage within the medial ganglionic eminence (GABA‐D1‐cKO), which include a subset of crucial cerebral cortical interneurons within the frontal cortex. Cell‐type specific loss of D1 receptor expression was validated by in situ hybridization. Neurobehavioral analyses of GABA‐D1‐cKO mice revealed normal patterns of locomotor activity, anxiety, and spatial and nonspatial memory. However, GABA‐D1‐cKO mice exhibit decreased immobility in the forced swim test and decreased latency to consume a palatable liquid in a novel stressful environment; these are both indicative of an antidepressant‐like effect. GABA‐D1‐cKO mice also show reduced basal plasma corticosterone levels and down‐regulation of the neurexin Cntnap4 in cerebral cortical interneurons. Conditional deletion of dopamine D1 receptors from telencephalic glutamatergic neurons (using Emx1‐Cre as a deletor) does not induce these phenotypes. These data suggest a new mechanism by which cerebral cortical interneurons may contribute to mood regulation and identify a new potential mechanism to exploit in the treatment and prevention of this prevalent brain disorder.Support or Funding InformationSupported by FSU College of Medicine and MH116429.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 of α7 nicotinic receptor positive allosteric modulator, PNU120596, on BDNF, NKCC1, and KCC2 expressions following LPS‐induced depressive‐like behavior in mice
Authors: Alzarea Sami , Rahman Shafiqur 
Published: June 2021

Previous evidence indicates that neuroinflammation plays a critical role in the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain‐derived neurotrophic factor (BDNF), Na‐K‐Cl cotransporter‐1 (NKCC1), and K‐Cl cotransporter‐2 (KCC2). However, the role of microglial α7 nicotinic acetylcholine receptors (nAChRs), exhibiting anti‐inflammatory function during the activation, on these mediators is unknown. The objective of the present study was to determine the effects of PNU120596 on BDNF, NKCC1, and KCC2 expressions in lipopolysaccharide (LPS)‐induced mouse model of MDD using Western blot analysis, immunofluorescence staining, and real‐time polymerase chain reaction. We also examined the pharmacological interaction between PNU120596 and ANA12, an antagonist of TrkB which is the primary receptor for BDNF, on LPS‐induced depressive‐like behavior using forced swim test (FST), tail suspension test (TST), and Y‐maze test. Systemic administration of LPS (1 mg/kg, i.p.) significantly increased BDNF protein expression and mRNA ratio of NKCC1 to KCC2, and decreased KCC2 mRNA expression in the hippocampus and prefrontal cortex, the brain regions implicated in MDD. The PNU120596 (1 or 4 mg/kg, i.p.) dose‐dependently prevented the LPS‐induced dysregulated BDNF, NKCC1, and KCC2 expressions in these brain regions. Combination treatment with PNU120596 (1 mg/kg, i.p.) and ANA12 (0.25 mg/kg, i.p.) prevented LPS‐induced increased immobility time during FST and TST and LPS‐induced decreased spontaneous alternations (%) during Y‐maze test. Overall, our results suggest that PNU120596 prevented LPS‐induced depressive‐like behavior by decreasing neuronal excitability by targeting microglial α7 nAChR in the hippocampus and prefrontal cortex. (Supported in part by grant from Saudi Arabian Cultural Mission, USA).Support or Funding InformationSupported in part by grant from Saudi Arabian Cultural Mission, USA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.