Neuroprotective and Antioxidant Properties of Different Novel Steroid-Derived Nitrones and Oximes on Cerebral Ischemia In Vitro

Despite the substantial global impact of ischemic stroke, current therapeutic options remain limited and only partially effective. To advance neuroprotective strategies that could improve the safety and efficacy of existing treatments while preserving brain tissue, we synthesized and evaluated seven new nitrones (<b>MC3</b>, <b>MC5</b>, <b>MC7</b>) and oximes (<b>MC1</b>, <b>MC2</b>, <b>MC4</b>, <b>MC6</b>) derived from different neuroactive steroids-ethisterone (<b>MC1-3</b>), mifepristone (<b>MC4-5</b>) and stanolone (<b>MC6-7</b>)-in an in vitro model of cerebral ischemia. Overall, these derivatives exhibited neuroprotective and antioxidant effects superior to those of the reference compounds cholesteronitrone <b>ChN2</b>, α-tert-butyl nitrone (<b>PBN</b>) and N-acetylcysteine (<b>NAC</b>). Notably, nitrones showed greater neuroprotective, anti-necrotic, and antioxidant potency than their corresponding oximes, regardless of the degree of molecular conjugation. Among them, the stanolone-derived nitrone <b>MC7</b>, which lacks conjugated double bonds, displayed the most balanced and robust profile, consistently enhancing cell viability, reducing necrotic cell death, and suppressing superoxide anion production. Consequently, <b>MC7</b> has been selected as a promising lead compound for further in vivo studies of cerebral ischemia.