| Summary: | Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (<b>ChN2</b>) and quinolylnitrone 23 (<b>QN23</b>), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both <b>ChN2</b> and <b>QN23</b> demonstrated significant neuroprotective effects (EC<sub>50</sub> = 0.66 ± 0.23 μM and EC<sub>50</sub> = 2.13 ± 0.47 μM, respectively) comparable to those of homo-bis-nitrone 6 (<b>HBN6</b>) and N-acetylcysteine (<b>NAC</b>) and superior to those of α-phenyl-N-tert-butylnitrone (<b>PBN</b>). While primarily derived from the nitrones’ anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers—especially in the case of <b>QN23</b>—also contribute to their neuroprotective effects.
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