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Neuroprotective efficacy of N-t-butylhydroxylamine (NtBHA) in transient focal ischemia in rats

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Abstract

The pharmacological or toxicological activities of the degradation products of drug candidates have been unaddressed during the drug development process. Ischemic stroke accounts for 80% of all strokes and is responsible for considerable mortality and disability worldwide. Despite decades of research on neuroprotective agents, tissue plasminogen activators (t-PA), a thrombolytic agent, remains the only approved acute stroke pharmacological therapy. NXY-059, a free radical scavenger, exhibited striking neuroprotective properties in preclinical models and met all the criteria established by the Stroke Academic Industry Roundtable (STAIR) for a neuroprotective agent. In phase 3 clinical trials, NXY-059 exhibited significant neuroprotective effects in one trial (SAINT-I), but not in the second (SAINT-II). Some have hypothesized that N-t-butyl hydroxylamine (NtBHA), a breakdown product of NXY-059 was the actual neuroprotective agent in SAINT-I and that changes to the formulation of NXY-059 to prevent its breakdown to NtBHA in SAINT -II was the reason for the lack of efficacy. We evaluated the neuroprotective effect of NtBHA in N-methyl-D-aspartate (NMDA)-treated primary neurons and in rat focal cerebral ischemia. NtBHA significantly attenuated infarct volume in rat transient focal ischemia, and attenuated NMDA-induced cytotoxicity in primary cortical neurons. NtBHA also reduced free radical generation and exhibited mitochondrial protection.

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Acknowledgements

This work was supported by a grant from the Ministry of Health and Welfare of Korea (HI14C2180) and grants from the National Research Foundation of Korea, supported by the Ministry of Science, ICT & Future Planning (NRF-2017R1C1B3002626). A.M. was partially supported/funded by the NIHR Sheffield Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care (DHSC).

Funding

This study was funded by Ministry of Health and Welfare (Grant number HI14C2180)and National Research Foundation of Korea (Grant number 2017R1C1B3002626).

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Authors and Affiliations

  1. College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, 15588, Ansan, Korea

    Eun-Sun Kim, Yusun Shin, Eun-Hye Kim, Donghyun Kim & Ok-Nam Bae

  2. Sheffield Institute for Translational Neuroscience, University of Sheffield, S10 2TN, Sheffield, UK

    Milena De Felice & Arshad Majid

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  1. Eun-Sun Kim
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Kim, ES., Shin, Y., Kim, EH. et al. Neuroprotective efficacy of N-t-butylhydroxylamine (NtBHA) in transient focal ischemia in rats. Toxicol Res. 38, 479–486 (2022). https://doi.org/10.1007/s43188-022-00131-7

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