scholarly journals WAY-100635 Alleviates Corneal Lesions Through 5-HT1A Receptor-ROS-Autophagy Axis in Dry Eye

2021 ◽  
Vol 8 ◽  
Author(s):  
Xujiao Zhou ◽  
Yiqin Dai ◽  
Zimeng Zhai ◽  
Jiaxu Hong
Keyword(s):  
Mouse Model ◽  
Receptor Antagonist ◽  
Inflammatory Cytokines ◽  
Dry Eye ◽  
Receptor Agonist ◽  
Ros Production ◽  
Fluorescein Sodium ◽  
Corneal Epithelial ◽  
Way 100635 ◽  
Chemokine Ligand

Purpose: To explore whether 5-HT1A receptors are involved in the dry eye disease (DED) mouse model and reveal its underlying mechanism.Methods: A C57BL/6J mouse DED model was established via the administration of 0.2% benzalkonium chloride twice a day for 14 days. Corneal fluorescein sodium staining score and Schirmer I test were checked before, and on days 7, 14, and 21 after treatment. The experiment was randomly divided into control, DED, 5-HT1A receptor agonist with or without N-acetylcysteine (NAC) and 5-HT1A receptor antagonist with or without NAC groups. The mRNA expression of inflammatory cytokines was measured by reverse transcription-quantitative polymerase chain reaction. Cellular reactive oxygen species (ROS) were detected by 2', 7'-dichlorodihydrofluorescein diacetate assays. Western blot analysis was used to measure the expression levels of autophagic proteins microtubule-associated protein 1 light chain 3 (LC3B-I/II) and autophagy-related gene 5 (ATG5).Results: 5-HT1A receptor agonist (8-OH-DPAT) increased corneal fluorescein sodium staining spots and 5-HT1A receptor antagonist (WAY-100635) decreased them. Treatment with 8-OH-DPAT was associated with the gene expression of more inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) compared with treatment with WAY-100635. An increased expression of LC3B-I/II and ATG5 was observed in corneal epithelial cells in the mouse model of DED. 8-OH-DPAT significantly enhanced the expression of LC3B-I/II and ATG5 by disrupting ROS levels. WAY-100635 alleviates autophagy by inhibiting ROS production.Conclusion: Excessive ROS release through 8-OH-DPAT induction can lead to impaired autophagy and increased inflammatory response in DED. WAY-100635 reduces corneal epithelial defects and inflammation in DED, as well as alleviates autophagy by inhibiting ROS production. The activation of the 5-HT1A receptor-ROS-autophagy axis is critically involved in DED development.

scholarly journals Nanomolar Potency Aminophenyltriazine CFTR Activator Reverses Corneal Epithelial Injury in a Mouse Model of Dry Eye

2020 ◽  
Vol 36 (3) ◽  
pp. 147-153 ◽  
Author(s):  
Xiaolan Chen ◽  
Sujin Lee ◽  
Tianyi Zhang ◽  
Tianying Duan ◽  
Neel D. Pasricha ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dry Eye ◽  
Epithelial Injury ◽  
Corneal Epithelial

scholarly journals The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

2021 ◽  
Author(s):  
◽  
Dane Aronsen
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Receptor Activation ◽  
Self Administration ◽  
Response Curves ◽  
Ru 24969 ◽  
Gr 127935 ◽  
Way 100635

<p>Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse.   Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed.  Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed.   Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors.   Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.</p>

scholarly journals The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

2021 ◽  
Author(s):  
◽  
Dane Aronsen
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Receptor Activation ◽  
Self Administration ◽  
Response Curves ◽  
Ru 24969 ◽  
Gr 127935 ◽  
Way 100635

<p>Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse.   Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed.  Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed.   Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors.   Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.</p>

scholarly journals Therapeutic Efficacy of Topically Applied Antioxidant Medicinal Plant Extracts in a Mouse Model of Experimental Dry Eye

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Won Choi ◽  
Jee Bum Lee ◽  
Lian Cui ◽  
Ying Li ◽  
Zhengri Li ◽  
...  
Keyword(s):  
T Cells ◽  
Medicinal Plant ◽  
Mouse Model ◽  
Cell Density ◽  
Dry Eye ◽  
Topical Application ◽  
Plant Extracts ◽  
Ros Production ◽  
Medicinal Plant Extracts ◽  
Goblet Cell Density

Purpose. To investigate the therapeutic effects of topical administration of antioxidant medicinal plant extracts in a mouse model of experimental dry eye (EDE).Methods. Eye drops containing balanced salt solution (BSS) or 0.001%, 0.01%, and 0.1% extracts were applied for the treatment of EDE. Tear volume, tear film break-up time (BUT), and corneal fluorescein staining scores were measured 10 days after desiccating stress. In addition, we evaluated the levels of interleukin- (IL-) 1β, tumor necrosis factor- (TNF-)α, IL-6, interferon- (IFN-)γ, and IFN-γassociated chemokines, percentage of CD4+C-X-C chemokine receptor type 3 positive (CXCR3+) T cells, goblet cell density, number of 4-hydroxy-2-nonenal (4-HNE) positive cells, and extracellular reactive oxygen species (ROS) production.Results. Compared to the EDE and BSS control groups, the mice treated with topical application of the 0.1% extract showed significant improvements in all clinical parameters, IL-1β, IL-6, TNF-α, and IFN-γlevels, percentage of CD4+CXCR3+ T cells, goblet cell density, number of 4-HNE-positive cells, and extracellular ROS production (P<0.05).Conclusions. Topical application of 0.1% medicinal plant extracts improved clinical signs, decreased inflammation, and ameliorated oxidative stress marker and ROS production on the ocular surface of the EDE model mice.

scholarly journals Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis

2021 ◽  
Vol 186 ◽  
pp. 108464
Author(s):  
Faik Imeri ◽  
Bisera Stepanovska Tanturovska ◽  
Aleksandra Zivkovic ◽  
Gaby Enzmann ◽  
Stephanie Schwalm ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Histamine H3 Receptor ◽  
H3 Receptor ◽  
S1p Receptor ◽  
Histamine H3

scholarly journals Anti-inflammatory effects of paeoniflorin from Paeonia lactiflora Pall. on human corneal epithelial cells and a mouse model of dry eye disease

RSC Advances ◽  
2019 ◽  
Vol 9 (23) ◽  
pp. 12998-13006 ◽  
Author(s):  
Mincong Zhao ◽  
Li Liu ◽  
Yating Zheng ◽  
Guangrong Liu ◽  
Biao Che ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Dry Eye ◽  
Dry Eye Disease ◽  
Eye Disease ◽  
Paeonia Lactiflora ◽  
Corneal Epithelial Cells ◽  
Corneal Epithelial ◽  
Human Corneal Epithelial Cells ◽  
Anti Inflammatory

Dry eye disease (DED) is characterized by increased osmolality of tears due to a lack of production or increased evaporation of tears.

scholarly journals Development of Lutein-Containing Eye Drops for the Treatment of Dry Eye Syndrome

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1801
Author(s):  
Yi-Zhou Chen ◽  
Zhi-Yu Chen ◽  
Yu-Jun Tang ◽  
Cheng-Han Tsai ◽  
Yu-Lun Chuang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Dry Eye ◽  
Dry Eye Syndrome ◽  
Eye Drops ◽  
Corneal Epithelial Cells ◽  
Corneal Epithelial ◽  
Tear Secretion ◽  
Tnf Α ◽  
Human Corneal Epithelial Cells

Dry eye syndrome (DES) is a common ophthalmological disease that decreases tear secretion and causes dryness, photophobia, pain, severe corneal rupture, and even blindness. Ocular and lacrimal gland inflammation is one of the pathological mechanisms underlying DES. Therefore, effective suppression of inflammation is a crucial strategy for the treatment of DES. Lutein, commonly found in healthy foods, has anti-inflammatory effects in corneal or retina-related cells and may be a potential therapy for DES. The addition of lutein to artificial tears (AT) as an eye-drop formulation for DES treatment in a mouse model was studied in the present work. Polyvinyl alcohol (PVA) was used as a thickener to increase the viscosity of eye drops to prolong drug retention on the ocular surface. A WST-8 assay in human corneal epithelial cells (HCE-2) showed that a concentration of <5 μM lutein (L5) and <1% PVA (P1) maintained the cell viability at 80%. A real-time PCR showed that the inflamed human corneal epithelial cells (HCECs) cocultured with L5P1 had downregulated expression of inflammatory genes such as IL-1β, IL-6, and TNF-α. In a benzalkonium chloride- (BAC) induced DES mouse model, AT/L5P1 could repair damaged corneas, elevate tear secretion, increase the number of goblet cells, and inhibit the production of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in the cornea. In conclusion, we demonstrate that lutein/PVA as eye drops could prolong the drug ocular retention time and effectively to decrease inflammation in DES mice. Therefore, lutein, obtained from eye drops, has a potential therapeutic role for DES.

scholarly journals Corneal epithelial proliferation and thickness in a mouse model of dry eye

2009 ◽  
Vol 89 (2) ◽  
pp. 166-171 ◽  
Author(s):  
Claudia Fabiani ◽  
Stefano Barabino ◽  
Saadia Rashid ◽  
M. Reza Dana
Keyword(s):  
Mouse Model ◽  
Dry Eye ◽  
Epithelial Proliferation ◽  
Corneal Epithelial

1887-P: The GLP-1 Receptor Agonist Liraglutide Improves Hepatic Inflammation and Fibrosis in a Mouse Model of NASH

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1887-P
Author(s):  
SOPHIE A. MONTANDON ◽  
EMMANUEL SOMM ◽  
CLAUDIO DE VITO ◽  
FRANÇOIS R. JORNAYVAZ
Keyword(s):  
Mouse Model ◽  
Receptor Agonist ◽  
Hepatic Inflammation
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