Neuroprotective efficacy of N-t-butylhydroxylamine (NtBHA) in transient focal ischemia in rats
- Authors
- Kim, Eun-Sun; Shin, Yusun; Kim, Eun-Hye; Kim, Donghyun; De Felice, Milena; Majid, Arshad; Bae, Ok-Nam
- Issue Date
- Oct-2022
- Publisher
- 한국독성학회
- Keywords
- Ischemic stroke; Neuroprotection; N-t-butylhydroxylamine (NtBHA)
- Citation
- Toxicological Research, v.38, no.4, pp 479 - 486
- Pages
- 8
- Indexed
- SCIE
SCOPUS
KCI
- Journal Title
- Toxicological Research
- Volume
- 38
- Number
- 4
- Start Page
- 479
- End Page
- 486
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/107898
- DOI
- 10.1007/s43188-022-00131-7
- ISSN
- 1976-8257
2234-2753
- 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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