Neuroprotective efficacy of N-t-butylhydroxylamine (NtBHA) in transient focal ischemia in rats
The pharmacological and toxicological effects of degradation products from drug candidates have often been overlooked during the drug development process. Ischemic stroke, which accounts for 80% of all strokes, leads to substantial mortality and disability worldwide. Despite extensive research on neuroprotective agents, tissue plasminogen activator (t-PA), a thrombolytic agent, remains the only approved pharmacological treatment for acute stroke. NXY-059, a free radical scavenger, demonstrated promising neuroprotective properties in preclinical studies and met all the criteria set by the Stroke Academic Industry Roundtable (STAIR) for neuroprotective agents. In phase 3 clinical trials, NXY-059 showed significant neuroprotective effects in one trial (SAINT-I) but failed to replicate this in a second trial (SAINT-II). It has been suggested that N-t-butyl hydroxylamine (NtBHA), a degradation product of NXY-059, was the true neuroprotective agent in SAINT-I, and modifications made to NXY-059 to prevent its breakdown to NtBHA in SAINT-II may have led to the lack of efficacy. We investigated the neuroprotective effects of NtBHA in primary neurons treated with N-methyl-D-aspartate (NMDA) and in a rat model of focal cerebral ischemia. NtBHA significantly reduced infarct volume in rat transient focal ischemia and mitigated NMDA-induced cytotoxicity in primary cortical neurons.