Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation

Jagadish, Swamy and Rajeev, N. and NaveenKumar, S. K. and Sharath Kumar, K. S. and Paul, Manoj and Hegde, Mahesh and Sadashiva, M. P. and Girish, K. S. and Rangappa, K. S. (2016) Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation. Molecular and Cellular Biochemistry, 414 (1). pp. 137-151. ISSN 1573-4919

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Official URL: http://dx.doi.org/10.1007/s11010-016-2667-4

Abstract

Thrombocytopenia is a major hematological concern in oxidative stress-associated pathologies and chronic clinical disorders, where premature platelet destruction severely affects the normal functioning of thrombosis and hemostasis. In addition, frequent exposure of platelets to chemical entities and therapeutic drugs immensely contributes in the development of thrombocytopenia leading to huge platelet loss, which might be fatal sometimes. Till date, there are only few platelet protective molecules known to combat thrombocytopenia. Hence, small molecule therapeutics are extremely in need to relieve the burden on limited treatment strategies of thrombocytopenia. In this study, we have synthesized a series of novel 3,4,5 trisubstituted isoxazole derivatives, among which compound 4a [4-methoxy-N’-(5-methyl-3-phenylisoxazole-4-carbonyl) benzenesulfonohydrazide] was found to significantly ameliorate the oxidative stress-induced platelet apoptosis by restoring various apoptotic markers such as ROS content, cytosolic Ca2+ levels, eIF2-α phosphorylation, mitochondrial membrane depolarization, cytochrome c release, caspase activation, PS externalization, and cytotoxicity markers. Additionally, compound 4a dose dependently inhibits collagen-induced platelet aggregation. Hence, compound 4a can be considered as a prospective molecule in the treatment regime of platelet activation and apoptosis and other clinical conditions of thrombocytopenia. Further studies might ensure the use of compound 4a as a supplementary therapeutic agent to treat, thrombosis and CVD-associated complications. Over all, the study reveals a platelet protective efficacy of novel isoxazole derivative 4a with a potential to combat oxidative stress-induced platelet apoptosis.

Item Type: Article
Additional Information: Unmapped bibliographic data: JO - Molecular and Cellular Biochemistry [Field not mapped to EPrints]
Subjects: Physical Sciences > Chemistry
Divisions: PG Campuses > Manasagangotri, Mysore > Chemistry
Depositing User: Ms. Manjula p
Date Deposited: 23 May 2017 05:49
Last Modified: 23 May 2017 05:49
URI: http://eprints.uni-mysore.ac.in/id/eprint/19437

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