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Article: Novel NADPH Oxidase-2 Inhibitors as Potential Anti-Inflammatory and Neuroprotective Agents.

Juric, Matea / Rawat, Varun / Amaradhi, Radhika / Zielonka, Jacek / Ganesh, Thota

2023 Volume 12, Issue 9

Abstract: A family of seven NADPH oxidase enzymes (Nox1-5, Duox1-2) has been implicated in a variety of diseases, including inflammatory lung diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Here, we report the results of our studies ... ...

Abstract	A family of seven NADPH oxidase enzymes (Nox1-5, Duox1-2) has been implicated in a variety of diseases, including inflammatory lung diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Here, we report the results of our studies aimed at developing novel brain-permeable Nox2 inhibitors with potential application as neuroprotective agents. Using cell-based assays, we identified a novel Nox2 inhibitor, TG15-132, that prevents PMA-stimulated oxygen consumption and reactive oxygen species (superoxide radical anion and hydrogen peroxide) formation upon acute treatment in differentiated HL60 cells. Long-term treatment with TG15-132 attenuates the induction of genes encoding Nox2 subunits, several inflammatory cytokines, and iNOS in differentiated THP-1 cells. Moreover, TG15-132 shows a relatively long plasma half-life (5.6 h) and excellent brain permeability, with a brain-to-plasma ratio (>5-fold) in rodent models. Additionally, TG15-132 does not cause any toxic effects on vital organs or blood biomarkers of toxicity in mice upon chronic dosing for seven days. We propose that TG15-132 may be used as a Nox2 inhibitor and a potential neuroprotective agent, with possible further structural modifications to increase its potency.
Language	English
Publishing date	2023-08-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12091660
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An Agonist Dependent Allosteric Antagonist of Prostaglandin EP2 Receptors.

Jiang, Chunxiang / Amaradhi, Radhika / Ganesh, Thota / Dingledine, Ray

ACS chemical neuroscience

2020 Volume 11, Issue 10, Page(s) 1436–1446

Abstract: All reported prostaglandin EP2 receptor antagonists have a purely orthosteric, competitive mode of action. Herein, we report the characterization of ... ...

Abstract	All reported prostaglandin EP2 receptor antagonists have a purely orthosteric, competitive mode of action. Herein, we report the characterization of compound
MeSH term(s)	Animals ; Humans ; Interleukin-6 ; Mice ; Prostaglandins ; Receptors, Prostaglandin E, EP2 Subtype ; Tumor Necrosis Factor-alpha
Chemical Substances	Interleukin-6 ; Prostaglandins ; Receptors, Prostaglandin E, EP2 Subtype ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2020-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.0c00078
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Azaindole therapeutic agents.

Motati, Damoder Reddy / Amaradhi, Radhika / Ganesh, Thota

Bioorganic & medicinal chemistry

2020 Volume 28, Issue 24, Page(s) 115830

Abstract: Azaindole structural framework is an integral part of several biologically active natural and synthetic organic molecules; and several FDA approved drugs for various diseases. In the last decade, quite a number of literature reports appeared describing ... ...

Abstract	Azaindole structural framework is an integral part of several biologically active natural and synthetic organic molecules; and several FDA approved drugs for various diseases. In the last decade, quite a number of literature reports appeared describing the pharmacology, biological activity and therapeutic applications of a variety of azaindole molecules. This prompted the organic and medicinal chemistry community to develop novel synthetic methods for various azaindoles and test them for a bioactivity against a variety of biological targets. Herein, we have summarized the biological activity of therapeutically advanced clinical candidates and several preclinical candidate drugs that contain azaindole structural moiety.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/therapeutic use ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Aza Compounds/chemistry ; Cell Proliferation/drug effects ; Humans ; Hypersensitivity/drug therapy ; Indoles/chemistry ; Indoles/pharmacology ; Indoles/therapeutic use ; Influenza A Virus, H1N1 Subtype/drug effects ; Neoplasms/drug therapy ; Neoplasms/pathology
Chemical Substances	Anti-Inflammatory Agents ; Antineoplastic Agents ; Aza Compounds ; Indoles
Language	English
Publishing date	2020-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2020.115830
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Article ; Online: Second-Generation Prostaglandin Receptor EP2 Antagonist, TG8-260, with High Potency, Selectivity, Oral Bioavailability, and Anti-Inflammatory Properties.

Amaradhi, Radhika / Mohammed, Shabber / Banik, Avijit / Franklin, Ronald / Dingledine, Raymond / Ganesh, Thota

ACS pharmacology & translational science

2022 Volume 5, Issue 2, Page(s) 118–133

Abstract: EP2, a G-protein-coupled prostaglandin- ... ...

Abstract	EP2, a G-protein-coupled prostaglandin-E
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.1c00255
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Article: Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection.

Ghimire, Roshan / Shrestha, Rakshya / Amaradhi, Radhika / Patton, Titus / Whitley, Cody / Chanda, Debarati / Liu, Lin / Ganesh, Thota / More, Sunil / Channappanavar, Rudragouda

bioRxiv : the preprint server for biology

2023

Abstract: SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory ... ...

Abstract	SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory responses
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.08.539929
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer's disease.

Banik, Avijit / Amaradhi, Radhika / Lee, Daniel / Sau, Michael / Wang, Wenyi / Dingledine, Raymond / Ganesh, Thota

Journal of neuroinflammation

2021 Volume 18, Issue 1, Page(s) 273

Abstract: Background: Alzheimer's disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being ... ...

Abstract	Background: Alzheimer's disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods: We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit-genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit-environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results: Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid-plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion: These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/pathology ; Anemia/blood ; Animals ; Blood Cell Count ; Cyclooxygenase 2/genetics ; Female ; Humans ; Inflammation Mediators/metabolism ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Transgenic ; Neuroglia/metabolism ; Neuroinflammatory Diseases/drug therapy ; Neuroinflammatory Diseases/pathology ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology ; Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors ; Sex Characteristics ; Signal Transduction/drug effects
Chemical Substances	Inflammation Mediators ; Lipopolysaccharides ; Receptors, Prostaglandin E, EP2 Subtype ; Cyclooxygenase 2 (EC 1.14.99.1)
Language	English
Publishing date	2021-11-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02297-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Temporal Expression of Neuroinflammatory and Oxidative Stress Markers and Prostaglandin E2 Receptor EP2 Antagonist Effect in a Rat Model of Epileptogenesis.

Rawat, Varun / Eastman, Clifford L / Amaradhi, Radhika / Banik, Avijit / Fender, Jason S / Dingledine, Raymond J / D'Ambrosio, Raimondo / Ganesh, Thota

ACS pharmacology & translational science

2022 Volume 6, Issue 1, Page(s) 128–138

Abstract: Traumatic brain injury (TBI) in patients results in a massive inflammatory reaction, disruption of blood-brain barrier, and oxidative stress in the brain, and these inciting features may culminate in the emergence of post-traumatic epilepsy (PTE). We ... ...

Abstract	Traumatic brain injury (TBI) in patients results in a massive inflammatory reaction, disruption of blood-brain barrier, and oxidative stress in the brain, and these inciting features may culminate in the emergence of post-traumatic epilepsy (PTE). We hypothesize that targeting these pathways with pharmacological agents could be an effective therapeutic strategy to prevent epileptogenesis. To design therapeutic strategies targeting neuroinflammation and oxidative stress, we utilized a fluid percussion injury (FPI) rat model to study the temporal expression of neuroinflammatory and oxidative stress markers from 3 to 24 h following FPI. FPI results in increased mRNA expression of inflammatory mediators including cyclooxygenase-2 (COX-2) and prostanoid receptor EP2, marker of oxidative stress (NOX2), astrogliosis (GFAP), and microgliosis (CD11b) in ipsilateral cortex and hippocampus. The analysis of protein levels indicated a significant increase in the expression of COX-2 in ipsilateral hippocampus and cortex post-FPI. We tested FPI rats with an EP2 antagonist TG8-260 which produced a statistically significant reduction in the distribution of seizure duration post-FPI and trends toward a reduction in seizure incidence, seizure frequency, and duration, hinting a proof of concept that EP2 antagonism must be further optimized for therapeutic applications to prevent epileptogenesis.
Language	English
Publishing date	2022-12-08
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.2c00189
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Pharmacological antagonism of EP2 receptor does not modify basal cardiovascular and respiratory function, blood cell counts, and bone morphology in animal models.

Rawat, Varun / Banik, Avijit / Amaradhi, Radhika / Rojas, Asheebo / Taval, Shashidharamurthy / Nagy, Tamas / Dingledine, Raymond / Ganesh, Thota

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 147, Page(s) 112646

Abstract: The EP2 receptor has emerged as a therapeutic target with exacerbating role in disease pathology for a variety of peripheral and central nervous system disorders. We and others have recently demonstrated beneficial effects of EP2 antagonists in ... ...

Abstract	The EP2 receptor has emerged as a therapeutic target with exacerbating role in disease pathology for a variety of peripheral and central nervous system disorders. We and others have recently demonstrated beneficial effects of EP2 antagonists in preclinical models of neuroinflammation and peripheral inflammation. However, it was earlier reported that mice with global EP2 knockout (KO) display adverse phenotypes on fertility and blood pressure. Other studies indicated that EP2 activation with an agonist has a beneficial effect of healing fractured bone in animal models. These results impeded the development of EP2 antagonists, and EP2 antagonism as therapeutic strategy. To determine whether treatment with EP2 antagonist mimics the adverse phenotypes of the EP2 global KO mouse, we tested two EP2 antagonists TG11-77. HCl and TG6-10-1 in mice and rats while they are on normal or high-salt diet, and by two different administration protocols (acute and chronic). There were no adverse effects of the antagonists on systolic and diastolic blood pressure, heart rate, respiratory function in mice and rats regardless of rodents being on a regular or high salt diet. Furthermore, chronic exposure to TG11-77. HCl produced no adverse effects on blood cell counts, bone-volume and bone-mineral density in mice. Our findings argue against adverse effects on cardiovascular and respiratory systems, blood counts and bone structure in healthy rodents from the use of small molecule reversible antagonists for EP2, in contrast to the genetic ablation model. This study paves the way for advancing therapeutic applications of EP2 antagonists against diseases involving EP2 dysfunction.
MeSH term(s)	Animals ; Blood Cell Count ; Bone Density/drug effects ; Bone and Bones/drug effects ; Cardiovascular Diseases/pathology ; Disease Models, Animal ; Female ; Hemodynamics/drug effects ; Indoles/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors ; Respiratory Rate/drug effects
Chemical Substances	Indoles ; Receptors, Prostaglandin E, EP2 Subtype ; TG6-10-1
Language	English
Publishing date	2022-01-26
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.112646
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Article ; Online: Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection

Ghimire, Roshan / Shrestha, Rakshya / Amaradhi, Radhika / Patton, Titus / Whitley, Cody / Chanda, Debarati / Liu, Lin / Ganesh, Thota / More, Sunil / Channappanavar, Rudragouda

bioRxiv

Abstract	SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory responses in-vivo are not well defined. CoVs possess single-stranded RNA (ssRNA) that is abundantly produced during infection and stimulates both antiviral interferon (IFN) and inflammatory cytokine/ chemokine responses. Therefore, in this study, using wild-type control and TLR7 deficient BALB/c mice infected with a mouse-adapted SARS-COV-2 (MA-CoV-2), we evaluated the role of TLR7 signaling in MA-CoV-2-induced antiviral and inflammatory responses and disease outcome. We show that TLR7-deficient mice are more susceptible to MA-CoV-2 infection as compared to infected control mice. Further evaluation of MA-CoV-2 infected lungs showed significantly reduced mRNA levels of antiviral type I and type III IFNs, IFN stimulated genes (ISGs, ISG15 and CXCL10), and several pro-inflammatory cytokines/chemokines in TLR7 deficient compared to control mice. Reduced lung IFN/ISG levels and increased morbidity/mortality in TLR7 deficient mice correlated with high lung viral titer. Detailed examination of total cells from MA-CoV-2 infected lungs showed high neutrophil count in TLR7 deficient mice compared to control mice. Additionally, blocking TLR7 activity post-MA-CoV-2 infection using a specific inhibitor also enhanced disease severity. In summary, our results conclusively establish that TLR7 signaling is protective during SARS-CoV-2 infection, and despite robust inflammatory response, TLR7-mediated IFN/ISG responses likely protect the host from lethal disease. Given similar outcomes in control and TLR7 deficient humans and mice, these results show that MA-CoV-2 infected mice serve as excellent model to study COVID-19.
Keywords	covid19
Language	English
Publishing date	2023-05-09
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.05.08.539929
Database	COVID19

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Article ; Online: Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

Ganesh, Thota / Banik, Avijit / Dingledine, Ray / Wang, Wenyi / Amaradhi, Radhika

Molecular pharmaceutics

2018 Volume 15, Issue 12, Page(s) 5809–5817

Abstract: The prostaglandin ... ...

Abstract	The prostaglandin E
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/immunology ; Cell Line ; Dinoprostone/immunology ; Dinoprostone/metabolism ; Drug Evaluation, Preclinical ; Endometriosis/drug therapy ; Endometriosis/immunology ; Female ; Half-Life ; Inflammation Mediators/immunology ; Inflammation Mediators/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasms/drug therapy ; Neoplasms/immunology ; Rats ; Receptors, Prostaglandin/metabolism ; Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors ; Receptors, Prostaglandin E, EP2 Subtype/immunology ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Receptors, Prostaglandin E, EP4 Subtype/metabolism ; Solubility ; Up-Regulation/drug effects ; Up-Regulation/immunology ; Water/chemistry
Chemical Substances	Anti-Inflammatory Agents ; Inflammation Mediators ; PTGER2 protein, human ; Receptors, Prostaglandin ; Receptors, Prostaglandin E, EP2 Subtype ; Receptors, Prostaglandin E, EP4 Subtype ; prostanoid D receptor 1, human ; Water (059QF0KO0R) ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2018-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.8b00764
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