Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats

Zikra Zulfiqar,1 Fawad Ali Shah,1 Shagufta Shafique,2 Abdullah Alattar,3 Tahir Ali,4 Arooj Mohsin Alvi,1 Sajid Rashid,2 Shupeng Li5 1Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 2National Center for Bioinformatics, Qua...

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Autores principales: Zulfiqar Z, Shah FA, Shafique S, Alattar A, Ali T, Alvi AM, Rashid S, Li S
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2020
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Acceso en línea:https://doaj.org/article/3993ac6521104e28ac67bcf2e6a69281
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id oai:doaj.org-article:3993ac6521104e28ac67bcf2e6a69281
record_format dspace
institution DOAJ
collection DOAJ
language EN
topic re-purposing
in silico docking
jnk3 kinase
mcao stroke
jnk3 inhibitors
neuroinflammation
brain degeneration
Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
spellingShingle re-purposing
in silico docking
jnk3 kinase
mcao stroke
jnk3 inhibitors
neuroinflammation
brain degeneration
Pathology
RB1-214
Therapeutics. Pharmacology
RM1-950
Zulfiqar Z
Shah FA
Shafique S
Alattar A
Ali T
Alvi AM
Rashid S
Li S
Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats
description Zikra Zulfiqar,1 Fawad Ali Shah,1 Shagufta Shafique,2 Abdullah Alattar,3 Tahir Ali,4 Arooj Mohsin Alvi,1 Sajid Rashid,2 Shupeng Li5 1Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 2National Center for Bioinformatics, Quaid-I-Azam University, Islamabad, Pakistan; 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; 4Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; 5State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of ChinaCorrespondence: Fawad Ali Shah; Shupeng Li Tel +92-51-2891835-8Fax +92-51-2890690Email fawad.shah@riphah.edu.pk; lisp@pkusz.edu.cnBackground: Stress-associated kinases are considered major pathological mediators in several incurable neurological disorders. Importantly, among these stress kinases, the c-Jun NH2-terminal kinase (JNK) has been linked to numerous neuropathological conditions, including oxidative stress, neuroinflammation, and brain degeneration associated with brain injuries such as ischemia/reperfusion injury. In this study, we adopted a drug repurposing/reprofiling approach to explore novel JNK3 inhibitors from FDA-approved medications to supplement existing therapeutic strategies.Materials and Methods: We performed in silico docking analysis and molecular dynamics simulation to screen potential candidates from the FDA approved drug library using the standard JNK inhibitor SP600125 as a reference. After the virtual screening, dabigatran, estazolam, leucovorin, and pitavastatin were further examined in ischemic stroke using an animal rodent model of focal cerebral ischemia using transient middle cerebral artery occlusion (t-MCAO). The selected drugs were probed for neuroprotective effectiveness by measuring the infarct area (%) and neurological deficits using a 28-point composite score. Biochemical assays including ELISA and immunohistochemical experiments were performed.Results: We obtained structural insights for dabigatran, estazolam, and pitavastatin binding to JNK3, revealing a significant contribution of the hydrophobic regions and significant residues of active site regions. To validate the docking results, the pharmacological effects of dabigatran, estazolam, leucovorin, and pitavastatin on MCAO were tested in parallel with the JNK inhibitor SP600125. After MCAO surgery, severe neurological deficits were detected in the MCAO group compared with the sham controls, which were significantly reversed by dabigatran, estazolam, and pitavastatin treatment. Aberrant morphological features and brain damage were observed in the ipsilateral cortex and striatum of the MCAO groups. The drugs restored the anti-oxidant enzyme activity and reduced the levels of oxidative stress-induced p-JNK and neuroinflammatory mediators such as NF-kB and TNF-ɑ in rats subjected to MCAO.Conclusion: Our results demonstrated that the novel FDA-approved medications attenuate ischemic stroke-induced neuronal degeneration, possibly by inhibiting JNK3. Being FDA-approved safe medications, the use of these drugs can be clinically translated for ischemic stroke-associated brain degeneration and other neurodegenerative diseases associated with oxidative stress and neuroinflammation.Keywords: re-purposing, in silico docking, JNK3 kinase, MCAO stroke, JNK3 inhibitors, neuroinflammation, brain degeneration
format article
author Zulfiqar Z
Shah FA
Shafique S
Alattar A
Ali T
Alvi AM
Rashid S
Li S
author_facet Zulfiqar Z
Shah FA
Shafique S
Alattar A
Ali T
Alvi AM
Rashid S
Li S
author_sort Zulfiqar Z
title Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats
title_short Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats
title_full Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats
title_fullStr Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats
title_full_unstemmed Repurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats
title_sort repurposing fda approved drugs as jnk3 inhibitor for prevention of neuroinflammation induced by mcao in rats
publisher Dove Medical Press
publishDate 2020
url https://doaj.org/article/3993ac6521104e28ac67bcf2e6a69281
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spelling oai:doaj.org-article:3993ac6521104e28ac67bcf2e6a692812021-12-02T13:55:19ZRepurposing FDA Approved Drugs as JNK3 Inhibitor for Prevention of Neuroinflammation Induced by MCAO in Rats1178-7031https://doaj.org/article/3993ac6521104e28ac67bcf2e6a692812020-12-01T00:00:00Zhttps://www.dovepress.com/repurposing-fda-approved-drugs-as-jnk3-inhibitor-for-prevention-of-neu-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Zikra Zulfiqar,1 Fawad Ali Shah,1 Shagufta Shafique,2 Abdullah Alattar,3 Tahir Ali,4 Arooj Mohsin Alvi,1 Sajid Rashid,2 Shupeng Li5 1Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 2National Center for Bioinformatics, Quaid-I-Azam University, Islamabad, Pakistan; 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; 4Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; 5State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of ChinaCorrespondence: Fawad Ali Shah; Shupeng Li Tel +92-51-2891835-8Fax +92-51-2890690Email fawad.shah@riphah.edu.pk; lisp@pkusz.edu.cnBackground: Stress-associated kinases are considered major pathological mediators in several incurable neurological disorders. Importantly, among these stress kinases, the c-Jun NH2-terminal kinase (JNK) has been linked to numerous neuropathological conditions, including oxidative stress, neuroinflammation, and brain degeneration associated with brain injuries such as ischemia/reperfusion injury. In this study, we adopted a drug repurposing/reprofiling approach to explore novel JNK3 inhibitors from FDA-approved medications to supplement existing therapeutic strategies.Materials and Methods: We performed in silico docking analysis and molecular dynamics simulation to screen potential candidates from the FDA approved drug library using the standard JNK inhibitor SP600125 as a reference. After the virtual screening, dabigatran, estazolam, leucovorin, and pitavastatin were further examined in ischemic stroke using an animal rodent model of focal cerebral ischemia using transient middle cerebral artery occlusion (t-MCAO). The selected drugs were probed for neuroprotective effectiveness by measuring the infarct area (%) and neurological deficits using a 28-point composite score. Biochemical assays including ELISA and immunohistochemical experiments were performed.Results: We obtained structural insights for dabigatran, estazolam, and pitavastatin binding to JNK3, revealing a significant contribution of the hydrophobic regions and significant residues of active site regions. To validate the docking results, the pharmacological effects of dabigatran, estazolam, leucovorin, and pitavastatin on MCAO were tested in parallel with the JNK inhibitor SP600125. After MCAO surgery, severe neurological deficits were detected in the MCAO group compared with the sham controls, which were significantly reversed by dabigatran, estazolam, and pitavastatin treatment. Aberrant morphological features and brain damage were observed in the ipsilateral cortex and striatum of the MCAO groups. The drugs restored the anti-oxidant enzyme activity and reduced the levels of oxidative stress-induced p-JNK and neuroinflammatory mediators such as NF-kB and TNF-ɑ in rats subjected to MCAO.Conclusion: Our results demonstrated that the novel FDA-approved medications attenuate ischemic stroke-induced neuronal degeneration, possibly by inhibiting JNK3. Being FDA-approved safe medications, the use of these drugs can be clinically translated for ischemic stroke-associated brain degeneration and other neurodegenerative diseases associated with oxidative stress and neuroinflammation.Keywords: re-purposing, in silico docking, JNK3 kinase, MCAO stroke, JNK3 inhibitors, neuroinflammation, brain degenerationZulfiqar ZShah FAShafique SAlattar AAli TAlvi AMRashid SLi SDove Medical Pressarticlere-purposingin silico dockingjnk3 kinasemcao strokejnk3 inhibitorsneuroinflammationbrain degenerationPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 13, Pp 1185-1205 (2020)