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Partial blood replacement ameliorates middle cerebral artery occlusion generated neurological aberrations by intervening TLR4 and NLRP3 cascades in rats

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Abstract

Acute ischemic stroke is a catastrophic medical condition that causes severe disability and mortality if the sufferer escapes treatment within a stipulated timeframe. While timely intervention with clot-bursting agents like tissue-plasminogen activators abrogates some post-stroke neurologic deficits, no neuroprotective therapy is yet promisingly addresses the post-recanalization neuroinflammation in post-stroke survivors. Herein, we investigated the effect of partial blood replacement therapy (BRT), obtained from healthy and treadmill-trained donor rats, on neurological deficits, and peripheral and central inflammatory cascades using the ischemia-reperfusion animal paradigm. The cerebral ischemia-reperfusion was induced in rats by occlusion of the middle cerebral artery (MCAO) for 90 min, followed by reperfusion. Rats underwent MCAO surgery displayed remarkable sensorimotor and motor deficits in rotarod, foot fault, adhesive removal, and paw whisker tests till 5 days post-surgery. These behavior abnormalities were ameliorated in the BRT-recipient MCAO rats. BRT also reduced the infarct volume and neuronal death in the ipsilateral hemisphere revealed by TTC and cresyl violet staining compared to the MCAO group. Rats received BRT infusion exhibited the reduced expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule-1 (Iba-1), and MyD88 on day 5 post-MCAO in immunohistochemistry and immunofluorescent assays. Moreover, elevated levels of toll-like receptor 4 (TLR4) and mRNA expression of IL-1β, TNF-α, matrix metalloproteinase-9 and NLRP3, and decreased levels of zonula occludens-1 in MCAO rats, were reversed following BRT. These findings suggest that the partial BRT may rescind MCAO-induced neurological dysfunctions and cerebral injury by intervening in the TLR4 and NLRP3 pathways in rats.

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Acknowledgements

The authors (ZR, SG and MPD) want to thank the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for financial support. NIPER.

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MPD also thanks funding from the DST-SERB, File number SRG/2020/002439.

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  1. Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India

    Ziaur Rahman, Shubham Ghuge & Manoj P. Dandekar

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ZR: Executed the study, prepared results, and drafted the manuscript; SG: assisted in preclinical study; MPD: Conceptualized, reviewed, and corrected the manuscript.

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Correspondence to Manoj P. Dandekar.

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Rahman, Z., Ghuge, S. & Dandekar, M.P. Partial blood replacement ameliorates middle cerebral artery occlusion generated neurological aberrations by intervening TLR4 and NLRP3 cascades in rats. Metab Brain Dis 38, 2339–2354 (2023). https://doi.org/10.1007/s11011-023-01259-7

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