Heterocyclic homoprostanoid derivative attenuates monoarthritis in rats

An in vitro and in vivo preclinical paradigm

Jayesh Mudgal, S. A. Manohara Reddy, Geetha Mathew, Anoop Kishore, C. Mallikarjuna Rao, Gopalan K. Nampurath

Research output: Contribution to journalArticle

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Abstract

From our lab, among the nineteen heterocyclic homoprostanoids (HHPs), three derivatives (compounds 3, 3b and 3c) exerted antioxidant and anti-inflammatory activity. Present study is an extension of the earlier work, and, is designed to establish their therapeutic potential in monoarthritis in rats. In addition, their possible mechanism of action would be investigated. A battery of in vitro tests such as lipopolysaccharide (LPS)-induced nitrite (NO)/reactive oxygen species (ROS) and NO/interleukin (IL)-6 generation in murine macrophages and whole blood (WhB), respectively were conducted. Later, in vitro cyclooxygenase (COX) enzyme inhibitory activity was also evaluated. All the tested compounds showed comparable efficacy against ROS and NO in LPS-stimulated murine macrophages. However, compound 3 did not exert inhibitory effect on LPS-induced NO/IL-6 generation in WhB assay. Compounds (3b and 3c) inhibited the NO generation in LPS-stimulated WhB. However, only compound 3b reversed the raised IL-6 levels in this assay. None of the test compounds inhibited COX iso-enzymes in the in vitro assay. All three HHPs showed comparable efficacy against carrageenan-induced paw inflammation. However, none of them exhibited any dose-dependent effect in this model. Based upon previous reports, compound 3c was explored against adjuvant-induced monoarthritis (AIA) in male Sprague-Dawley rats, where it exerted promising therapeutic effect. In addition to radiological and histological examinations of tibio-tarsal joint, various parameters such as chronic inflammation/pain, clinical score, interleukin (IL)-6 levels and complete blood cell profile were evaluated in AIA rats. Chronic treatment with 3c halted the disease progression in rats, improved the overall health of animals, as demonstrated by haematological, clinical scoring and joint examinations (radiological and histopathological). Inhibitory effect on elevated IL-6 in AIA rats suggested the possible mechanism of 3c on cytokine signalling. Overall, the study supports the anti-arthritic potential of compound 3c.

Original languageEnglish
Pages (from-to)320-329
Number of pages10
JournalEuropean Journal of Pharmaceutical Sciences
Volume111
DOIs
Publication statusPublished - 01-01-2018

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Interleukin-6
Lipopolysaccharides
Prostaglandin-Endoperoxide Synthases
Reactive Oxygen Species
Tarsal Joints
Macrophages
Inflammation
Carrageenan
Therapeutic Uses
Enzymes
Nitrites
Chronic Pain
Arthritis
Sprague Dawley Rats
Disease Progression
Blood Cells
Anti-Inflammatory Agents
Antioxidants
Joints
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

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title = "Heterocyclic homoprostanoid derivative attenuates monoarthritis in rats: An in vitro and in vivo preclinical paradigm",
abstract = "From our lab, among the nineteen heterocyclic homoprostanoids (HHPs), three derivatives (compounds 3, 3b and 3c) exerted antioxidant and anti-inflammatory activity. Present study is an extension of the earlier work, and, is designed to establish their therapeutic potential in monoarthritis in rats. In addition, their possible mechanism of action would be investigated. A battery of in vitro tests such as lipopolysaccharide (LPS)-induced nitrite (NO)/reactive oxygen species (ROS) and NO/interleukin (IL)-6 generation in murine macrophages and whole blood (WhB), respectively were conducted. Later, in vitro cyclooxygenase (COX) enzyme inhibitory activity was also evaluated. All the tested compounds showed comparable efficacy against ROS and NO in LPS-stimulated murine macrophages. However, compound 3 did not exert inhibitory effect on LPS-induced NO/IL-6 generation in WhB assay. Compounds (3b and 3c) inhibited the NO generation in LPS-stimulated WhB. However, only compound 3b reversed the raised IL-6 levels in this assay. None of the test compounds inhibited COX iso-enzymes in the in vitro assay. All three HHPs showed comparable efficacy against carrageenan-induced paw inflammation. However, none of them exhibited any dose-dependent effect in this model. Based upon previous reports, compound 3c was explored against adjuvant-induced monoarthritis (AIA) in male Sprague-Dawley rats, where it exerted promising therapeutic effect. In addition to radiological and histological examinations of tibio-tarsal joint, various parameters such as chronic inflammation/pain, clinical score, interleukin (IL)-6 levels and complete blood cell profile were evaluated in AIA rats. Chronic treatment with 3c halted the disease progression in rats, improved the overall health of animals, as demonstrated by haematological, clinical scoring and joint examinations (radiological and histopathological). Inhibitory effect on elevated IL-6 in AIA rats suggested the possible mechanism of 3c on cytokine signalling. Overall, the study supports the anti-arthritic potential of compound 3c.",
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Heterocyclic homoprostanoid derivative attenuates monoarthritis in rats : An in vitro and in vivo preclinical paradigm. / Mudgal, Jayesh; Manohara Reddy, S. A.; Mathew, Geetha; Kishore, Anoop; Mallikarjuna Rao, C.; Nampurath, Gopalan K.

In: European Journal of Pharmaceutical Sciences, Vol. 111, 01.01.2018, p. 320-329.

Research output: Contribution to journalArticle

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T1 - Heterocyclic homoprostanoid derivative attenuates monoarthritis in rats

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AU - Mudgal, Jayesh

AU - Manohara Reddy, S. A.

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AU - Nampurath, Gopalan K.

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